1h-imidazo[4,5-c]quinolinone derivatives

ABSTRACT

The invention relates to the use of 1H-imidazo[4,5-c]quinolinone derivatives and salts thereof in the treatment of protein and/or lipid kinase dependent diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases; 1H-imidazo[4,5-c]quinolinone derivatives for use in the treatment of protein and/or lipid kinase dependent diseases; a method of treatment against said diseases, comprising administering the 1H-imidazo[4,5-c]quinolinone derivatives to a warm-blooded animal, especially a human; pharmaceutical preparations comprising an 1H-imidazo[4,5-c]quinolinone derivative, especially for the treatment of a protein and/or lipid kinase dependent disease; novel 1H-imidazo[4,5-c]quinolinone derivatives; and a process for the preparation of the novel 1H-imidazo[4,5-c]quinolinone derivatives.

RELATED APPLICATIONS

This application claims priority to U.S. Application Ser. No. 61/184,141 filed 4 Jun. 2009, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The invention relates to imidazoquinolinones, salts and prodrugs thereof, processes for their preparation, their use in the treatment of protein or lipid kinase dependent diseases and in particular phosphatidylinositol-3-kinase (PI3K) dependent diseases, their use, either alone or in combination with at least one additional therapeutic agent and optionally in combination with a pharmaceutically acceptable carrier, for the manufacture of pharmaceutical preparations, use of the pharmaceutical preparations for the treatment of protein or lipid kinase dependant diseases and in particular PI3K dependent diseases, and a method of treatment of said diseases, comprising administering the imidazoquinolinones to a warm-blooded animal, especially a human. The invention also relates to pharmaceutical preparations comprising an imidazoquinolinone of the invention, either alone or in combination with at least one additional therapeutic agent, and optionally in combination with a pharmaceutically acceptable carrier.

SUMMARY OF THE INVENTION

The phosphatidylinositol-3-kinases superfamily comprises 4 different PI3K related lipid or protein kinases. Class I, II and III are lipid kinases that differ from their substrate specificities whereas class IV PI3K also called PI3-kinase-related protein kinase (PIKK) are protein kinases. Class I phosphatidylinositol-3-kinases comprise a family of lipid kinases that catalyze the transfer of phosphate to the D-3′ position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate (PIP₂) and phosphoinositol-3,4,5-triphosphate (PIP₃) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane ((Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol 17:615 (2001)). Of the two Class I PI3Ks, Class IA PI3Ks are heterodimers composed of a catalytic p110 subunit (α, β, δ isoforms) constitutively associated with a regulatory subunit that can be p85α, p55α, p50α, p85β or p55γ. The Class IB sub-class has one family member, a heterodimer composed of a catalytic p110γ subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Suire et al., Curr. Bio. 15:566 (2005)). The modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class IA PI3Ks. Class IB PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001)). Consequently, the resultant phospholipid products of class I PI3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)).

In many cases, PIP2 and PIP3 recruit Akt, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell 69:413-423 (1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2:489 (2002)). Aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3′ position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110 isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human cancers. Furthermore, mutations and translocation of p85, that serve to up-regulate the p85-p110 complex have been described in human cancers. Also, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at significant frequencies in a wide diversity of human cancers (Kang at al., Proc. Natl. Acad. Sci. USA 102:802 (2005); Samuels et al., Science 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations show that deregulation of phosphoinositol-3 kinase and the upstream and downstream components of this signaling pathway is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 436:792 (2005); Hennessey et al., Nature Rev. Drug Disc. 4:988-1004 (2005)).

The mammalian target of rapamycin (mTOR) is a member of the class IV PI3K. mTOR assembles a signaling network that transduces nutrient signals and various other stimuli to regulate a wide range of cellular functions including cell growth, proliferation, survival, autophagy, various types of differentiation and metabolism. In mammalian cells, the mTOR protein is found complexed in two distinct entities called mTORC1 and mTORC2. The mTORC1 complex, that is to say mTOR associated with raptor, has been the matter of numerous studies. It is mTORC1 that integrates nutrient and growth factor input, and is in turn responsible for cell growth regulation, mainly through protein synthesis regulators such as 4EBP1 or RPS6. Activation of mTORC1 requires input from active PI3K and Akt kinases meaning that mTORC1 is a downstream effector of the PI3K pathway. mTOR when associated in the mTOR complex 2 (mTORC2) has been shown to be responsible for the activation of Akt by phosphorylation of S473 (Akt 1 numbering) (Sarbassov et al., Science 307:7098 (2005)). mTORC2 is hence here considered as an upstream activator of Akt. Interestingly mTOR can therefore be considered as being important both upstream and downstream of Akt. Taken together, mTOR can be regarded as a downstream effector and an upstream activator of Akt depending on its association with the mTOCR1 and mTORC2 complex, respectively. mTOR catalytic inhibition might therefore represent a unique way of introducing a very strong block in the PI3K-Akt pathway, by addressing both upstream and downstream effectors. Syndromes with an established or potential molecular link to disregulation of mTOR kinase activity are, for instance, described in “K. Inoki et al.; Disregulation of the TSC-mTOR pathway in human disease, Nature Genetics, vol 37, 19-24”; “D. M. Sabatini; mTOR and cancer: insights into a complex relationship, Nature Reviews, vol. 6, 729-734”; and in “B. T. Hennessy et al.; Exploiting the PI3K/Akt pathway for cancer drug discovery, Nature Reviews, vol. 4, 988-1004”, and are as follows:

-   -   Organ or tissue transplant rejection, e.g. for the treatment of         recipients of e.g. heart, lung, combined heart-lung, liver,         kidney, pancreatic, skin or corneal transplants;         graft-versus-host disease, such as following bone marrow         transplantation;     -   Restenosis     -   Tuberous sclerosis     -   Lymphangioleiomyomatosis     -   Retinitis pigmentosis     -   Autoimmune diseases including encephalomyelitis,         insulin-dependent diabetes mellitus, lupus, dermatomyositis,         arthritis and rheumatic diseases     -   Steroid-resistant acute Lymphoblastic Leukaemia     -   Fibrotic diseases including scleroderma, pulmonary fibrosis,         renal fibrosis, cystic fibrosis     -   Pulmonary hypertension     -   Immunomodulation     -   Multiple sclerosis     -   VHL syndrome     -   Carney complex     -   Familial adenonamtous polyposis     -   Juvenile polyposis syndrome     -   Birt-Hogg-Duke syndrome     -   Familial hypertrophic cardiomyopathy     -   Wolf-Parkinson-White syndrome     -   Neurodegenarative disorders such as Parkinson's, Huntingtin's,         Alzheimer's and dementias caused by tau mutations,         spinocerebellar ataxia type 3, motor neuron disease caused by         SOD1 mutations, neuronal ceroid lipofucinoses/Batten disease         (pediatric neurodegeneration)     -   wet and dry macular degeneration     -   muscle wasting (atrophy, cachexia) and myopathies such as         Danon's disease.

bacterial and viral infections including M. tuberculosis, group A streptococcus, HSV type I, HIV infection

-   -   Neurofibromatosis including Neurofibromatosis type 1,     -   Peutz-Jeghers syndrome         or further any combinations thereof.

Compounds with an inhibitory activity on mTORC1 have shown benefit in immunomodulation and in treating proliferative diseases such as advance renal cell carcinoma or Tubero-Sclerosis (TSC) germ line mutation associated disorders.

The catalytic inhibition of mTOR Ser/Thr kinase activity or class I PI3 kinases activity and in particular dual class I PI3-kinase(s) and mTOR kinase inhibition is considered to be useful for the treatment of PI3K/Akt/mTOR pathway dependent diseases.

The efficacy of a dual PI3 kinase/mTOR inhibitor in malignant glioma has been recently described (Cancer Cell 9, 341-349).

In view of the above, inhibitors of class I and/or IV PI3Ks are considered to be of value in the treatment of proliferative disease and other disorders.

WO2003/097641, WO2005/054237, WO2005/054238 and WO2006/122806 describe imidazoquinolines for use in the treatment of protein kinase dependent diseases.

WO 2008/103636 describes imidazoquinolines as dual lipid kinase and mTor inhibitors.

It has now been found that the imidazoquinolinones derivatives of the formula (I) given below have advantageous pharmacological properties and inhibit, for example, lipid or protein kinases such as PI4K (phosphatidylinositol 4-kinase) and/or PI3 kinases (phosphatidylinositol 3-kinases), for example, inhibition of the PI3K superfamily which comprises PI3Kalpha, PI3 Kbeta, PI3 Kdelta, PI3 Kgamma and mTOR, or one or more of the individual kinase members thereof. The class IV PI3K also called PI3-kinase-related protein kinase (PIKK) includes DNA-PK, ATM, ATR, hSMG-1 and mTOR. In particular, preferably imidazoquinolinones of the formula (I) given below show a high degree of selectivity in favour of one or more of the class I-IV PI3K against other protein kinases, such as the receptor tyrosine kinases and/or the Ser/Thr kinases outside of the PIKK family in the biochemical and/or in the cellular assay. In addition, the imidazoquinolinones of the formula (I) preferably display a favourable solubility and/or membrane permeability at physiological pH. Hence, the compounds of formula (I) are suitable, for example, to be used in the treatment of diseases dependent on PI3 kinase, especially proliferative diseases such as tumor diseases, leukaemias, and myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia, and proliferative skin diseases including basal cell carcinoma, squamous cell carcinoma and actinic keratosis and other benign hyperproliferative skin disorders caused by inflammation such as psoriasis or as a result of dysregulation of fibroblasts such as skin fibrosis, scleroderma or keloids.

DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides compounds of the formula (I)

wherein

-   -   X is O or S;     -   Y is CH or N;     -   R¹ is a substituted or unsubstituted 5-membered heteroaryl;     -   R² is hydrogen, lower alkyl or lower alkenyl;     -   R³ is a substituted or unsubstituted aryl or heterocyclyl; and     -   R⁴, R⁵ and R⁶ are hydrogen;         or a pharmaceutically acceptable salt, solvate, hydrate or         prodrug thereof.

The present invention is also directed to use of compounds of formula (I) in the treatment of protein and/or lipid kinase dependent diseases; use of compounds of formula (I) for the manufacture of pharmaceutical preparations for the treatment of protein and/or lipid kinase dependent diseases and in particular PI3K superfamily (especially class I PI3K and/or mTOR) dependent diseases; methods of treating protein and/or lipid kinase dependant diseases and in particular PI3K superfamily (especially class I PI3K and/or mTOR) dependent diseases comprising administering imidazoquinolinone compounds of the formula (I) to a warm-blooded animal, especially a human; pharmaceutical preparations comprising an imidazoquinolinone compound of the formula (I), especially for the treatment of a protein and/or lipid kinase dependant disease and in particular a PI3K superfamilly (especially class I PI3K and/or mTOR) dependent disease; a process for the manufacture of the novel imidazoquinolinone compounds of the formula (I); the manufacture of a pharmaceutical preparation for the treatment of protein and/or lipid kinase dependant diseases and in particular PI3K superfamily (especially class I PI3K and/or mTOR) dependent diseases, and novel intermediates for their manufacture. Preferably, the PI3K superfamily dependent diseases are class I PI3K and/or mTOR dependent diseases.

The invention may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. As used herein, the terms “including”, “containing” and “comprising” are used herein in their open, non-limiting sense.

Any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different stereoisomeric forms such as different enantiomeric forms. If at least one asymmetrical carbon atom is present in a compound of the formula I, such a compound may exist in optically active form or in the form of a mixture of optical isomers, e.g. in the form of a racemic mixture. Thus an asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. All optical isomers and their mixtures, including the racemic mixtures, are part of the present invention. Thus, any given formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof. Furthermore, certain structures may exist as geometric isomers (e.g. cis and trans isomers), as tautomers, or as atropisomers. For example, substituents at a double bond or a ring may be present in cis-(=Z-) or trans (=E-) form. The compounds of the invention may thus be present as mixtures of isomers or preferably as pure isomers, preferably as enantiomer-pure diastereomers or pure enantiomers.

Any formula given herein is intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴, C¹⁵N, ³¹P, ³²P, ¹⁸F ³⁵S, ³⁶Cl, ¹²⁵I respectively. Various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹³C, and ¹⁴C are incorporated. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F or labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere. In other words, where a variable appears more than once, the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula (where one or more up to all more general expressions in embodiments characterized as preferred above or below can be replaced with a more specific definition, thus leading to a more preferred embodiment of the invention, respectively).

Where the plural form (e.g. compounds, salts, pharmaceutical preparations, diseases and the like) is used, this includes the singular (e.g. a single compound, a single salt, a single pharmaceutical preparation, a single disease, and the like). “A compound” does not exclude that (e.g. in a pharmaceutical formulation) more than one compound of the formula (I) (or a salt thereof) is present.

Salts are preferably the pharmaceutically acceptable salts of compounds of formula (I) if they are carrying salt-forming groups.

The salts of compounds of formula (I) are preferably pharmaceutically acceptable salts; acids/bases required to form the salts are generally known in the field.

Salt-forming groups in a compound of formula (I) are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, e.g., amino; a secondary amino group not forming a peptide bond or a pyridyl radical, may form acid addition salts, e.g., with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid; or with suitable organic carboxylic or sulfonic acids, e.g., aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid; or amino acids, such as arginine or lysine; aromatic carboxylic acids, such as benzoic acid; 2-phenoxy-benzoic acid; 2-acetoxy-benzoic acid; salicylic acid; 4-aminosalicylic acid; aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid; heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid; aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethanesulfonic acid; or aromatic sulfonic acids, e.g., benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed.

Compounds of formula (I) having acidic groups, a carboxy group or a phenolic hydroxy group, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium or calcium salts; or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, e.g., triethylamine or tri(2-hydroxyethyl)-amine, or heterocyclic bases, e.g., N-ethyl-piperidine or N,N′-dimethylpiperazine. Mixtures of salts are possible.

Compounds of formula (I) having both acidic and basic groups can form internal salts.

For the purposes of isolation or purification, as well as in the case of compounds that are used further as intermediates, it is also possible to use pharmaceutically-unacceptable salts, e.g., the picrates. Only pharmaceutically-acceptable, non-toxic salts may be used for therapeutic purposes, however, and those salts are therefore preferred.

Owing to the close relationship between the novel compounds in free form and in the form of their salts, including those salts that can be used as intermediates, e.g., in the purification of the novel compounds or for the identification thereof, any reference hereinbefore and hereinafter to the free compounds shall be understood as including the corresponding salts, where appropriate and expedient.

Compounds of the present invention may also form solvates and hydrates, and as such any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding solvate and/or hydrate of the compound of formula (I), as appropriate and expedient.

The present invention also relates to pro-drugs of a compound of formula (I) that convert in vivo to the compound of formula (I) as such. Any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding pro-drugs of the compound of formula (I), as appropriate and expedient.

The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:

The prefix “lower” denotes a radical having 1 carbon atom up to and including a maximum of 7 carbon atoms, especially 1 carbon atom up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single- or multiple-branching.

Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably fluoro, chloro or bromo.

Alkyl preferably has 1 up 12 carbon atoms (C₁₋₁₂alkyl) and is linear or branched one or more times; in particular alkyl is lower alkyl, especially C₁-C₄alkyl. For example, alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, with particular preference given to methyl, ethyl, n-propyl, iso-propyl, n-butyl and iso-butyl. Lower alkyl, for example, is represented as C₁-C₇alkyl, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl, lower alkyl is especially represented as C₁-C₄alkyl, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, with preference given to methyl, ethyl or propyl.

Alkyl, in particular lower alkyl, is unsubstituted or substituted, preferably by one or more substituents independently selected from those mentioned below under “substituted”. Exemplary substituents include, but are not limited to hydroxy, alkoxy, aryl, heterocyclyl, cycloalkyl, halogen, amino and nitro. An example of a substituted alkyl is halo-alkyl, such as halomethyl, for example fluoromethyl, e.g. trifluoromethyl. Another example of a substituted alkyl is hydroxymethyl or hydroxyethyl. A further example of a substituted alkyl is alkoxyalkyl, such as methoxyethyl or methoxypropyl. The alkoxyalkyl may be further substituted, for example to give benzyloxyethyl or benzyloxypropyl.

Alkyl may also be cyclic as defined below under “cycloalkyl”. Cycloalkyl may also be a substituent to alkyl. Cycloalkyl-lower alkyl is preferably lower alkyl that is substituted (preferably terminally) by unsubstituted or substituted cycloalkyl as defined below. An example of cycloalkyl as a substituent to alkyl is alkandiyl-cycloalkyl, such as alkandiyl-cycloloweralkyl, e.g. alkandiyl-cyclopropyl, e.g. —CH₂-cyclopropyl.

Aryl-lower alkyl is preferably lower alkyl that is substituted (preferably terminally or in 1-position) by unsubstituted or substituted aryl as defined below. Aryl-lower alkyl is especially phenyl-lower alkyl, such as benzyl (i.e. phenylmethyl) or phenylethyl, especially 1-phenylethyl.

Heterocyclyl-lower alkyl is preferably lower alkyl that is substituted (preferably terminally) by unsubstituted or substituted heterocyclyl as defined below.

Each alkyl part of other groups like “alkoxy”, “alkoxyalkyl”, “alkoxyalkoxy”, “alkoxycarbonyl”, “alkoxy-carbonylalkyl”, “alkylsulfonyl”, “alkylsulfonamide”, “alkylsulfinyl”, “alkylamino”, “halogenalkyl” shall have the same meaning as described in the above-mentioned definition of “alkyl”, including the prefix ‘lower’, including substitutions thereof.

For example, aryl-lower alkoxy is preferably lower alkoxy that is substituted (preferably terminally on the alkyl part) by unsubstituted or substituted aryl as defined below. Aryl-lower alkoxy is especially phenyl-lower alkoxy, such as phenyl methoxy (i.e. benzoxy) or phenyl ethoxy.

Alkoxyalkoxy is, for example, methoxyethoxy, or methoxypropoxy, and may include further substitutions e.g. by aryl such as phenyl, for example to give phenylmethoxyethoxy (alternatively stated benzoxy-ethoxy) or phenylmethoxypropoxy (alternatively stated benzoxy-propoxy).

Alkandiyl is a straight-chain or branched-chain divalent alkyl group. It preferably represents a straight-chain or branched-chain C₁₋₁₂ alkandiyl, particularly preferably represents a straight-chain or branched-chain C₁₋₆ alkandiyl; for example, methandiyl (—CH₂—), 1,2-ethanediyl (—CH₂—CH₂—), 1,1-ethanediyl ((—CH(CH₃)—), 1,1-, 1,2-, 1,3-propanediyl and 1,1-, 1,2-, 1,3-, 1,4-butanediyl, with particular preference given to methandiyl, 1,1-ethanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl.

Alkenyl is preferably a moiety with one or more double bonds and preferably has 2-12 carbon atoms; it is linear or branched one or more times (as far as possible in view of the number of carbon atoms). Preferred is C₂-C₇alkenyl, especially C₃-C₄alkenyl, such as allyl or crotyl. For example, —CH═CH—, —CH═C(CH₃)—, —CH═CH—CH₂—, —C(CH₃)═CH—CH₂—, —CH═C(CH₃)—CH₂—, —CH═CH—C(CH₃)H—, —CH═CH—CH═CH—, —C(CH₃)═CH—CH═CH—, —CH═C(CH₃)—CH═CH—. Alkenyl can be unsubstituted or substituted, especially by one or more, more especially up to three of the substituents mentioned below under “substituted”. Substituents, such as amino or hydroxy (with free dissociable hydrogen) preferably are not bound to carbon atoms that participate at a double bond, and also other substituents that are not sufficiently stable are preferably excluded. Unsubstituted alkenyl, in particular, C₂-C₇alkenyl is preferred.

Alkynyl is preferably a moiety with one or more triple bonds and preferably has 2-12 carbon atoms; it is linear of branched one or more times (as far as possible in view of the number of carbon atoms). Preferred is C₂-C₇alkynyl, especially C₃-C₄alkynyl, such as ethynyl or propyn-2-yl. Alkynyl can be unsubstituted or substituted, especially by one or more, more especially up to three of the substituents mentioned below under “substituted”. Substituents, such as amino or hydroxy (with free dissociable hydrogen) preferably are not bound to carbon atoms that participate at a triple bond, and also other substituents that are not sufficiently stable are preferably excluded. Unsubstituted alkynyl, in particular, C₂-C₇alkynyl is preferred.

Cycloalkyl is a saturated, monocyclic, fused polycyclic, or spiro polycyclic, carbocycle having from 3 to 12 ring atoms per carbocycle. Cycloalkyl is preferably C₃-C₁₀cycloalkyl, and includes cyclo lower alkyl, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; cycloalkyl being unsubstituted or substituted by one or more substituents, especially 1-3 substituents independently selected from the group consisting of the substituents defined below under “substituted”.

Cycloalkenyl is preferably C₅-C₁₀cycloalkenyl, especially cyclopentenyl, cyclohexenyl or cycloheptenyl; cycloalkenyl being unsubstituted or substituted by one or more substituents, especially 1-3 substituents, independently selected from the group consisting of the substituents defined below under “substituted”.

Aryl refers to an unsaturated carbocyclic aromatic ring system, preferably, having a ring system of not more than 16 carbon atoms, especially not more than 10 carbon atoms, e.g. having 6 to 16, preferably 6 to 10 ring carbon atoms, is preferably mono- or bi-cyclic, and is unsubstituted or substituted preferably as defined below under “substituted”. For example, aryl is selected from phenyl or naphthyl, preferably phenyl, and is preferably in each case unsubstituted or substituted with substituents described under “substituted”, in particular from the group consisting of halo, especially fluoro, chloro, bromo or iodo, in particular fluoro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino, mono or disubstituted amino, especially alkyl-substituted amino, hydroxyalkyl-substituted amino or alkoxyalkyl-substituted amino, e.g. dimethyl amino, 2-hydroxyethyl amino or 2-methoxyethylamino; cyclic amino, such as aziridinyl, azetidinyl or pyrrolidinyl; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; alkylamino-lower alkyl, e.g. methylaminomethyl, ethylaminomethyl, methylaminoethyl or ethylaminoethyl; dialkylamino-loweralkyl, e.g. dimethylaminomethyl, dimethylaminoethyl, methylethylaminomethyl, methylethylaminoethyl, diethylaminomethyl or diethylaminoethyl; cycloalkylaminoalkyl, e.g. cyclopropylaminomethyl, cyclopropylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclopentylaminom ethyl or cyclopentylaminoethyl; dicycloalkylaminoalkyl, e.g. dicyclopropylaminomethyl, dicyclopropylaminoethyl, cyclopropylcyclobutylaminomethyl or cyclopropylcyclobutylaminoethyl; alkylcycloalkylaminoalkyl, e.g. cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclopropylethylaminomethyl or cyclopropylethylaminoethyl; lower alkoxy, e.g., methoxy, ethoxy or propyloxy (e.g. iso-propyloxy); hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; alkoxy lower alkoxy, e.g. methoxyethoxy or ethoxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl, 2-cyanopropyl, 2-cyano-2-methylpropyl or 3-cyanopropyl; amidino; N-hydroxyamidino; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; nitro; carboxylic acid; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide (or lower alkylaminosulfonyl or N,N-di-loweralkyl aminosulfonyl, e.g. methylaminosulfonyl or dimethylaminosulfonyl) or pyrrolidine-1-sulfonyl; lower alkyl sulfonyl amino, e.g. methylsulfonylamino; lower alkyl sulfonylalkandiylamino, e.g. methylsulfonylmethylamino; lower alkylsulfonyl-N-lower alkylamino, e.g. methylsulfonyl-N-methylamino; acylamino, e.g. acetylamino, acyl lower alkyl amino, e.g. acetyl methyl amino; [1,3]dioxolo; substituted [1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl; substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl and dimethylcarbamoyl. The aryl group may also be substituted with a substituted or unsubstituted heterocycle, preferably a 4-7 membered ring, e.g. 1H-tetrazolyl (in particular 1H-tetrazol-5-yl), pyrazol, imidazole, triazole, azetidinyl, pyrrolidinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, triazolonyl or methylimidazolyl. The aryl group may also be substituted with heterocyclyl lower alkyl, heteroaryl or heteroaryl lower alkyl as defined hereinbelow. Preferred unsubstituted or substituted aryl is selected from phenyl; hydroxyphenyl, e.g., 2-, 3- or 4-hydroxyphenyl; methoxyphenyl, e.g., 2-, 3- or 4-methoxyphenyl or 3,4-dimethoxyphenyl; ethoxyphenyl, e.g., 2-, 3- or 4-ethoxyphenyl or 3,4-diethoxyphenyl; propoxyphenyl (e.g. iso-propoxyphenyl) such as 3-propoxyphenyl (e.g. 3-iso-propoxyphenyl); methoxy ethoxy-phenyl, e.g. 3-methoxy-4-ethoxy phenyl or 4-methoxy-3-ethoxy phenyl, or other lower-alkoxy phenyl, e.g. 3-methoxy-4-(2-methoxy ethoxy)-phenyl; halo-alkoxy-phenyl, e.g. fluoro-(iso-propoxy)-phenyl, e.g. 2-fluoro-3-(iso-propoxy)-phenyl; hydroxyalkoxy phenyl, e.g. 2-hydroxyethoxy-phenyl; hydroxy alkoxy phenyl, e.g. 3-methoxy-4-hydroxy phenyl; halo-hydroxy-phenyl, e.g. fluoro-hydroxy-phenyl such as 3-fluoro-5-hydroxy-phenyl; hydroxy-haloalkyl-phenyl, e.g. hydroxy-fluoroalkyl-phenyl such as 3-hydroxy-5-trifluoromethyl-phenyl; 2,2-difluoro-benzo[1,3]dioxolo, benzene sulfonamide, e.g. 3-N-methylbenzenesulfonamide, 3-N,N-dimethylbenzenesulfonamide, 3-(pyrrolidine-1-sulfonyl)-phenyl, N-phen-3-yl-methanesulfonamide or N-methyl-N-phen-3-yl-methanesulfonamide; alkyl-sulfonyl phenyl, e.g. 3-methanesulfonylphenyl; benzamide e.g. 3- or 4-benzamide, 3- or 4-N-methyl-benzamide or 2-, 3- or 4-N,N-dimethyl-benzamide; pyrazol-phenyl, e.g. 4-pyrazol-phenyl; imidazol-phenyl, e.g. (1H-imidazol-2-yl)phenyl.

Heterocyclyl refers to a heterocyclic radical that is unsaturated (=carrying the highest possible number of conjugated double bonds in the ring(s) e.g. heteroaryl, for example pyrazolyl, pyridyl, pyrimidinyl), saturated or partially saturated in the bonding ring and is preferably a monocyclic or in a broader aspect of the invention bicyclic ring; has 3-16 ring atoms, more preferably 4-10 ring atoms, such as 6, 9 or 10 ring atoms, wherein 1-4 ring atoms, especially one or two ring atoms are a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; the bonding ring preferably having 4-12 ring atoms, especially 4-7 ring atoms, for example 6 ring atoms, For bicyclic heterocyclyl, the ring which is bonded to the rest of the molecule of formula (I) may or may not contain a heteroatom. Also, for bicyclic heterocyclyl, both rings (i.e. both the bonding ring and non-bonding ring) may contain a heteroatom.

In an embodiment, heterocyclyl refers to a heterocyclic radical that is unsaturated (=carrying the highest possible number of conjugated double bonds in the ring(s) e.g. heteroaryl, for example pyrazolyl, pyridyl, pyrimidinyl), saturated or partially saturated in the bonding ring and is preferably a monocyclic or in a broader aspect of the invention bicyclic ring; has 3-16 ring atoms, more preferably 4-10 ring atoms, wherein at least in the ring bonding to the radical of the molecule of formula (I) one or more, preferably 1-4 ring atoms, especially one or two ring atoms are a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; the bonding ring preferably having 4-12 ring atoms, especially 4-7 ring atoms, for example 6-10 ring atoms, especially for heteroaryl, such as 6, 9 or 10 ring atoms.

In an embodiment, the heterocyclyl may be unsubstituted, or substituted by one or more, especially 1-4 substituents independently selected from the group consisting of the substituents defined below under “substituted”; especially being a heterocyclyl radical selected from the group consisting of oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, tetrahydrothiophene, indolyl, 1-methyl-2,3-dihydro-1H-indolyl, 2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, azetidinyl, pyranyl, thiopyranyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, indolizinyl, isoindolyl, 3H-indolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, phthalazinyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, furazanyl, chromenyl, isochromanyl, chromanyl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl (also termed 1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl), 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl (also termed 1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-oneyl), 1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl (also termed 1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl), 1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl (also termed 1-(2-methoxyethyl)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl), 3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-imidazo[4,5-b]pyridinyl, 2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl, 2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl, 2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, 2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl and 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl; each of these heterocycle radicals being unsubstituted or substituted by one to two radicals selected from the substituents described under “substituted”, in particular from the group consisting of halo, especially fluoro, chloro, bromo or iodo, more especially fluoro or chloro, in particular fluoro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino, mono or disubstituted amino, especially alkyl-substituted amino, hydroxyalkyl-substituted amino or alkoxyalkyl-substituted amino, e.g. dimethyl amino, 2-hydroxyethyl amino or 2-methoxyethyl amino; cyclic amino, such as aziridinyl, azetidinyl or pyrrolidinyl; substituted cyclic amino, e.g. hydroxy cyclic amino; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; alkylamino-lower alkyl, e.g. methylaminomethyl, ethylaminomethyl, methylaminoethyl or ethylaminoethyl; dialkylamino-loweralkyl, e.g. dimethylaminomethyl, dimethylaminoethyl, methylethylaminomethyl, methylethylaminoethyl, diethylaminomethyl or diethylaminoethyl; cycloalkylaminoalkyl, e.g. cyclopropylaminomethyl, cyclopropylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclopentylaminomethyl or cyclopentylaminoethyl; dicycloalkylaminoalkyl, e.g. dicyclopropylaminomethyl, dicyclopropylaminoethyl, cyclopropylcyclobutylaminomethyl or cyclopropylcyclobutylaminoethyl; alkylcycloalkylaminoalkyl, e.g. cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclopropylethylaminomethyl or cyclopropylethylaminoethyl; lower alkoxy, e.g., methoxy, ethoxy or propyloxy; cycloalkoxy, e.g. cyclobutoxy; lower-alkoxyalkyl, e.g. methoxymethyl, methoxypropyl, ethoxypropyl; hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower cycloalkyl, e.g. hydroxy cyclopentyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; alkoxy lower alkoxy, e.g. methoxyethoxy or ethoxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl, 2-cyanopropyl, 2-cyano-2-methylpropyl or 3-cyanopropyl; cyano lower cycloalkyl, e.g cyano cyclobutyl; amidino; N-hydroxyamidino; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; nitro; carboxylic acid; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide or pyrrolidine-1-sulfonyl; alkylsulfonylamino, e.g. methylsulfonylamino; alkylsulfonylalkylamino, e.g. methylsulfonylmethylamino; acylamino (also termed alkyl carbonyl amino), e.g. acetylamino; acyl alkyl amino, e.g. acetyl methyl amino; alkylcarbonylaminoalkyl, e.g. methylcarbonylaminomethyl; alkylaminocarbonylalkyl e.g. methylaminocarbonylmethyl; alkylcarbonyl-N-alkylamino, e.g. methylcarbonyl-N-methylamino; [1,3]dioxolo; substituted [1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl (also termed aminocarbonyl); substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl, ethyl carbamoyl, iso-propyl carbamoyl or alkoxyalkyl-substituted carbamoyl (also termed alkoxyalkylaminocarbonyl), e.g. 2-methoxyethylcarbamoyl. The heterocycle group may also be substituted with another substituted or unsubstituted heterocycle, preferably a 4-7 membered ring, e.g. 1H-tetrazolyl (in particular 1H-tetrazol-5-yl), pyrazol, imidazole, triazole, azetidinyl, pyrrolidinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, triazolonyl, methylimidazolyl or morpholino. The heterocycle group may also be substituted with heterocyclyl lower alkyl, heteroaryl or heteroaryl lower alkyl as defined herein.

In another embodiment, the heterocyclyl may be unsubstituted, or substituted by one or more, especially 1-4 substituents independently selected from the group consisting of the substituents defined below under “substituted”; especially being a heterocyclyl radical selected from the group consisting of oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, tetrahydrothiophene, indolyl, 1-methyl-2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, azetidinyl, pyranyl, thiopyranyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, indolizinyl, isoindolyl, 3H-indolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, phthalazinyl, naphthyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, furazanyl, chromenyl, isochromanyl and chromanyl and; each of these heterocycle radicals being unsubstituted or substituted by one to two radicals selected from the substituents described under “substituted”, in particular from the group consisting of halo, especially fluoro, chloro, bromo or iodo, more especially fluoro or chloro, in particular fluoro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino, mono or disubstituted amino, especially alkyl-substituted amino, hydroxyalkyl-substituted amino or alkoxyalkyl-substituted amino, e.g. dimethyl amino, 2-hydroxyethyl amino or 2-methoxyethyl amino; cyclic amino, such as aziridinyl, azetidinyl or pyrrolidinyl; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; alkylamino-lower alkyl, e.g. methylaminomethyl, ethylaminomethyl, methylaminoethyl or ethylaminoethyl; dialkylamino-loweralkyl, e.g. dimethylaminomethyl, dimethylaminoethyl, methylethylaminomethyl, methylethylaminoethyl, diethylaminomethyl or diethylaminoethyl; cycloalkylaminoalkyl, e.g. cyclopropylaminomethyl, cyclopropylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclopentylaminom ethyl or cyclopentylaminoethyl; dicycloalkylaminoalkyl, e.g. dicyclopropylaminomethyl, dicyclopropylaminoethyl, cyclopropylcyclobutylaminomethyl or cyclopropylcyclobutylaminoethyl; alkylcycloalkylaminoalkyl, e.g. cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclopropylethylaminomethyl or cyclopropylethylaminoethyl; lower alkoxy, e.g., methoxy, ethoxy or propyloxy; hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; alkoxy lower alkoxy, e.g. methoxyethoxy or ethoxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl, 2-cyanopropyl, 2-cyano-2-methylpropyl or 3-cyanopropyl; amidino; N-hydroxyamidino; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; nitro; carboxylic acid; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide or pyrrolidine-1-sulfonyl; alkylsulfonylamino, e.g. methylsulfonylamino; alkylsulfonylalkylamino, e.g. methylsulfonylmethylamino; acylamino, e.g. acetylamino; acyl alkyl amino, e.g. acetyl methyl amino; [1,3]dioxolo; substituted [1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl; substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl. The heterocycle group may also be substituted with another substituted or unsubstituted heterocycle, preferably a 4-7 membered ring, e.g. 1H-tetrazolyl (in particular 1H-tetrazol-5-yl), pyrazol, imidazole, triazole, azetidinyl, pyrrolidinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, triazolonyl or methylimidazolyl. The heterocycle group may also be substituted with heterocyclyl lower alkyl, heteroaryl or heteroaryl lower alkyl as defined herein.

In an embodiment, very preferred heterocyclic groups, which may be substituted or unsubstituted, include indolyl, 1-methyl-2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, pyrazolyl, pyrazinyl, quinolyl, quinoxalyl, 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl, 2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl, and 2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl each of which may be unsubstituted or substituted.

In an further embodiment, very preferred heterocyclic groups, each of which may be substituted or unsubstituted, include 1-methyl-2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, pyrazolyl, pyrazinyl, quinolyl, 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl, 2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl, and 2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl.

In another embodiment, heterocyclic groups, which may be substituted or unsubstituted, include indolyl, 1-methyl-2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, pyrazolyl, pyrazinyl, quinolyl, quinoxalyl, each of which may be unsubstituted or substituted.

In an embodiment, unsubstituted or substituted heterocyclyl is selected from pyridyl; alkylpyridyl, in particular lower-alkylpyridyl, e.g. methylpyridyl, e.g., 2-, 3- or 4-methylpyridyl, especially 2-methylpyridyl or 3-methylpyridyl; alkoxypyridyl, in particular lower-alkoxypyridyl, e.g. methoxypyridyl, e.g., 2-, 3- or 4-methoxypyridyl, especially 2-methoxypyridyl or 3-methoxypyridyl or di-methoxypyridyl, e.g. 2,3-dimethoxypyridyl, or ethoxypyridyl, e.g., 2-, 3- or 4-ethoxypyridyl especially 2-ethoxypyridyl or 3-ethoxypyridyl or di-ethoxypyridyl e.g. 2,3-diethoxypyridyl, or propyloxypyridyl, e.g., 2- or 3-propyloxypyridyl or isopropyloxypyridyl, e.g., 2- or 3-isopropyloxypyridyl; cycloalkyloxypyridyl, e.g. 2- or 3-cyclobutyloxypyridyl; (haloalkoxy)pyridyl e.g. 3-(1,3-difluoropropan-2-yloxy)-pyridyl or 3-(2-fluoroethan-1-yloxy)-pyridyl or 3-(difluoromethyloxy)-pyridyl; cycloalkylalkoxypyridyl, e.g. cyclopropylmethoxy-pyridyl, e.g. 2 or 3-cyclopropylmethoxy-pyridyl; alkoxyalkylpyridyl, e.g. methoxymethylpyridyl, e.g. 2 or 3-methoxymethylpyridyl or ethoxymethylpyridyl or 2-methoxy-prop-2-yl or 2-ethoxy-prop-2-yl; alkoxyalkoxypyridyl, in particular methoxyethoxypyridyl, e.g. 2 or 3-methoxyethoxypyridyl; (alkyl)(alkoxyalkoxy)pyridyl, e.g. (methyl)(methoxyethoxy)pyridyl; benzyloxyalkoxypyridyl, in particular benzyloxyethoxypyridyl or benzyloxypropoxypyridyl, e.g. 2-benzyloxyethoxypyridyl or 3-benzyloxypropoxypyridyl; hydroxyalkylpyridyl, e.g. 2 or 3-(2-hydroxyethyl)-pyridyl or hydroxypentylpyridyl e.g. 3-(3-hydroxypentyl)-pyridyl or hydroxypropylpyridyl, e.g. 3-(2-hydroxyprop-2-yl)-pyridyl or hydroxy-1,1-dimethyl-ethylpyridyl; hydroxycycloalkylpyridyl, e.g. 3-(1-hydroxycyclopentyl)-pyridyl; hydroxyfluoroalkylpyridyl, e.g. hydroxyfluoropropylpyridyl; aminoalkylpyridyl, e.g. aminomethylpyridyl; alkyl-sulfonyl pyridyl, e.g. methanesulfonylpyridyl, especially 3-methanesulfonylpyridyl; hydroxyalkoxypyridyl, e.g. 2-(2-hydroxyethoxy)-pyridyl or 2-(3-hydroxypropoxy)-pyridyl; hydroxyalkylpyridyl, e.g. hydroxymethylpyridyl, especially 2-(hydroxymethyl)-pyridyl; alkoxycarbonyl pyridyl, e.g. methoxycarbonylpyridyl, especially 2-methoxycarbonyl-pyridyl; aminopyridyl, e.g. 2- or 3-aminopyridyl; alkylaminopyridyl, in particular loweralkylaminopyridyl, e.g. 2-, 3- or 4-methylaminopyridyl, especially 2- or 3-methylaminopyridyl, 2-, 3- or 4-ethylaminopyridyl, especially 2- or 3-ethylaminopyridyl, e.g. 2- or 3-(1- or 2-propyl)aminopyridyl; dialkylaminopyridyl, in particular di-loweralkylaminopyridyl, e.g. 2-, 3- or 4-dimethylaminopyridyl, especially 2-dimethylaminopyridyl or 2-, 3- or 4-diethylaminopyridyl, especially 2- or 3-diethylaminopyridyl or e.g. 2-, 3- or 4-ethylmethylaminopyridyl especially 2-ethylmethylaminopyridyl or 3-ethylmethylaminopyridyl or e.g. 2-, 3- or 4-isopropylmethylaminopyridyl, especially 2-isopropylmethylaminopyridyl or 3-isopropylmethylaminopyridyl; cycloalkylaminopyridyl, e.g. cyclobutylaminopyridyl; (N-alkyl-N-cycloalkylamino)pyridyl, e.g. (N-methyl-N-cyclobutylamino)pyridyl; (alkyl)(amino)pyridyl, e.g. (loweralkyl)(amino)pyridyl, in particular (methyl)(amino)pyridyl such as 2-methyl-3-amino-pyridyl or (ethyl)(amino) pyridyl such as 2-ethyl-3-amino-pyridyl; (halo)(amino)pyridyl, e.g. (fluoro)(amino)pyridyl or (chloro)(amino)pyridyl; (halo)(alkylamino)pyridyl, e.g. (fluoro)(methylamino)pyridyl, (fluoro)(ethylamino)pyridyl; (halo)(dialkylamino)pyridyl, e.g. (fluoro)(dimethylamino)pyridyl; (halo)(hydroxyalkyl)pyridyl, e.g. (chloro)(hydroxymethyl)pyridyl; (alkoxy)(alkyl)pyridyl e.g. (methoxy)(methyl)pyridyl or (ethoxy)(methyl)pyridyl, or (propoxy)(methyl)pyridyl or (propoxy)(ethyl)pyridyl or (ethoxy)(ethyl)pyridyl; (alkoxy)(alkoxy)pyridyl e.g. (propoxy)(methoxy)pyridyl or (propoxy)(ethoxy)pyridyl or (methoxy)(methoxy)pyridyl or (ethoxy)(methoxy)pyridyl; (alkoxy)(alkoxyalkyl)pyridyl e.g. (isopropoxy)(methoxymethyl)pyridyl or (methoxy)(methoxymethyl)pyridyl or (methoxy)(ethoxymethyl)pyridyl or (ethoxy)(methoxymethyl)pyridyl; (alkoxy)(deuteroalkoxy-alkyl)pyridyl e.g. (ethoxy)(trideuteromethoxymethyl)pyridyl; (alkoxy)(hydroxyalkyl)pyridyl e.g. (isopropoxy)(hydroxymethyl)pyridyl or (methoxy)(hydroxymethyl)pyridyl, such as 3-methoxy-2-hydroxymethyl-pyridyl or 2-methoxy-3-hydroxymethyl-pyridyl or (ethoxy)(hydroxymethyl)pyridyl, such as 3-ethoxy-2-hydroxymethyl-pyridyl; (haloalkoxy)(alkyl)pyridyl e.g. (halo-isopropoxy)(methyl)pyridyl, such as 3-(1,3-difluoropropan-2-yloxy)-2-(methyl)-pyridyl; (haloalkoxy)(hydroxyalkyl)pyridyl e.g. 3-(1,3-difluoropropan-2-yloxy)-2-(hydroxymethyl)-pyridyl; (alkoxyalkoxy)(hydroxyalkyl)pyridyl, e.g. (methoxyethoxy)(hydroxymethyl)pyridyl, such as 3-methoxyethoxy-2-hydroxymethyl-pyridyl (in particular 3-methoxyethoxy-2-hydroxymethyl-pyrid-5-yl); (alkyl)(alkylamino)pyridyl, e.g. (methyl)(ethylamino)pyridyl such as 2-methyl-3-ethylamino-pyridyl or (methyl)(methylamino)pyridyl such as 3-methyl-2-methylamino-pyridyl or (ethyl)(ethylamino)pyridyl such as 2-ethyl-3-ethylamino-pyridyl or (ethyl)(isopropylamino)pyridyl such as 2-ethyl-3-isopropylamino-pyridyl; (alkyl)(di-alkylamino)pyridyl, e.g. (methyl)(N-methyl-N-ethylamino)pyridyl such as 2-methyl-3-(N-methyl-N-ethylamino)-pyridyl or (methyl)(N,N-dimethylamino)pyridyl such as 2-methyl-3-(N,N-dimethylamino)-pyridyl; cycloaminopyridyl, e.g. azetidinylpyridyl, especially 2-azetidin-1-yl-pyridyl or pyrrolidinylpyridyl, especially 2-pyrrolidin-2-ylpyridyl; cyclic ether-substituted amino-pyridyl, e.g. tetrahydro-pyranylamino-pyridyl; hydroxy-cycloaminopyridyl, e.g. hydroxy-pyrrolidinylpyridyl; loweralkoxy-cycloaminopyridyl, e.g. methoxy-pyrrolidinylpyridyl; hydroxyalkylaminopyridyl, e.g. 2-(2-hydroxyethylamino)-pyridyl; (alkyl)(hydroxy)pyridyl, e.g. 2-(methyl)-3-(hydroxy)-pyridyl or 2-(ethyl)-3-(hydroxy)-pyridyl; (hydroxyalkyl)(alkylamino)pyridyl, e.g. (hydroxymethyl)(ethylamino)-pyridyl, e.g. or (hydroxymethyl)(methylamino)-pyridyl; (hydroxyalkyl)(amino)pyridyl, e.g. (hydroxymethyl)(amino)-pyridyl; (alkoxyalkyl)(alkylamino)pyridyl, e.g. (methoxymethyl)(ethylamino)-pyridyl, or (methoxymethyl)(methylamino)-pyridyl, or (ethoxymethyl)(ethylamino)-pyridyl; (alkoxyalkyl)(amino)pyridyl, e.g. (ethoxymethyl)(amino)-pyridyl, or (methoxymethyl)(amino)-pyridyl; amino-haloloweralkyl-pyridyl, e.g. amino-trifluoromethyl-pyridyl, especially 2-amino-3-trifluoromethyl-pyridyl; alkylamino-haloalkyl-pyridyl, e.g. methylamino-trifluoromethyl-pyridyl or e.g. ethylamino-trifluoromethyl-pyridyl; haloalkyl-deuteroloweralkylamino-pyridyl, e.g. trifluoromethyl-trideuteromethylamino-pyridyl; haloalkylpyridinyl, in particular haloloweralkylpyridyl, especially, 2-, 3- or 4-trifluoromethylpyridyl, most especially 2-trifluoromethylpyridyl; cyanoalkylpyridinyl, e.g. cyanopropylpyridyl; cyanocycloalkylpyridinyl, e.g. cyanocyclobutylpyridyl; halopyridyl, in particular fluoropyridyl, especially 2-fluoropyridyl; halo-alkoxy-pyridyl, e.g. fluoro-methoxy-pyridyl such as 3-fluoro-2-methoxy-pyridyl; carbamoylpyridyl, especially 2-(carbamoyl)pyridyl; alkyl-substituted carbamoyl, e.g. methylcarbamoyl, especially 2-(methylcarbamoyl)pyridyl; piperazinylpyridyl, e.g. 1-piperazinylpyridyl; N-alkylpiperazinylpyridyl, e.g. N-methylpiperazinylpyridyl; alkylsulfonamidopyridyl, e.g. methylsulfonamidopyridyl; dialkylsulfonamidopyridyl, e.g. dimethylsulfonamidopyridyl; (alkylsulfonamido)(alkyl)pyridyl e.g. (methylsulfonamido)(methyl)pyridyl; (alkylsulfonamido)(halo)pyridyl e.g. (methylsulfonamido)(chloro)pyridyl; (alkylsulfonamidoalkyl)pyridyl e.g. (methylsulfonamidomethyl)pyridyl; dialkylsulfonamido(alkyl)pyridyl, e.g. dimethylsulfonamido(methyl)pyridyl; 3H-tetrazol-5-yl pyridyl, e.g. 2-(3H-tetrazol-5-yl)pyridyl (in particular 2-(3H-tetrazol-5-yl)pyrid-5-yl); alkylcarbonylaminoalkylpyridyl, e.g. methylcarbonylaminomethylpyridyl; (halo)(alkylcarbonylamino)pyridyl, e.g. (chloro)(methylcarbonylamino)pyridyl; (alkoxy)(alkylcarbonylamino)pyridyl, e.g. (methoxy)(methylcarbonylamino)pyridyl or (ethoxy)(methylcarbonylamino)pyridyl; (alkoxy)(alkylcarbonyl-N-alkylamino)pyridyl, e.g. (methoxy)(methylcarbonyl-N-methylamino)pyridyl or (ethoxy)(methylcarbonyl-N-methylamino)pyridyl; (alkoxy)(nitro)pyridyl, e.g. (methoxy)(nitro) pyridyl; (alkoxy)(cyano) pyridyl, e.g. (methoxy)(cyano) pyridyl; (alkoxy)(amino)pyridyl, e.g. (methoxy)(amino)pyridyl; (alkoxy)(alkylamino)pyridyl, e.g. (methoxy)(ethylamino)pyridyl; (alkoxyalkyl)(alkylamino)pyridyl, e.g. (methoxymethyl)(methylamino)pyridyl, or (methoxymethyl)(ethylamino)pyridyl; (alkoxy)(alkylaminocarbonyl)pyridyl, e.g. (methoxy)(methylaminocarbonyl)pyridyl; alkylaminocarbonylalkylpyridyl, e.g. methylaminocarbonylmethylpyridyl; (amino)(alkylaminocarbonyl)pyridyl, e.g. (amino)(methylaminocarbonyl)pyridyl, or (amino)(ethylaminocarbonyl)pyridyl or (amino)(isopropylaminocarbonyl)pyridyl; (amino)(alkoxyalkylaminocarbonyl)pyridyl, e.g. (amino)(methoxyethylaminocarbonyl)pyridyl; (alkylamino)(alkylaminocarbonyl)pyridyl, e.g. (methylamino)(ethylaminocarbonyl)pyridyl; (alkoxy)(aminocarbonyl)pyridyl, e.g. (methoxy)(aminocarbonyl)pyridyl; (alkoxy)(hydroxycarbonyl)pyridyl, e.g. (methoxy)(hydroxycarbonyl)pyridyl; morpholinylpyridinyl, e.g. morpholin-4-ylpyridinyl; (1H-pyrazolyl)-pyridinyl, e.g. (1H-pyrazol-1yl)-pyridinyl; loweralkylsubstituted(1H-imidazol-1-yl)-pyridinyl, e.g. methyl-substituted(1H-imidazol-1-yl)-pyridinyl; pyrimidinyl; loweralkylaminopyrimidinyl, e.g. 2- or 4-methylaminopyrimidinyl or 2- or 4-ethylaminopyrimidinyl; di-loweralkylaminopyrimidinyl, e.g. 2- or 4-methylethylaminopyrimidinyl, 2- or 4-dimethylaminopyrimidinyl, especially 2-dimethylaminopyrimidinyl; alkoxypyrimidinyl, in particular methoxypyrimidinyl or ethoxypyrimidinyl, e.g. 2-methoxypyrimidinyl or 2-ethoxypyrimidinyl; di-alkoxypyrimidinyl, e.g. 2,4-dimethoxypyrimidinyl; (alkylamino)(alkoxy)pyrimidinyl, e.g. (methylamino)(methoxy)pyrimidinyl or (ethylamino)(methoxy)pyrimidinyl; cycloaminopyrimidinyl, e.g. pyrrolidinylpyrimidinyl; aminopyrimidinyl, in particular 2-aminopyrimidinyl; alkylaminopyrimidinyl, e.g. 2-methylaminopyrimidinyl; dialkylaminopyrimidinyl, e.g. 2-dimethylaminopyrimidinyl; 1H-pyrrolo[2,3-b]pyridinyl; 1-methyl-1H-pyrrolo[2,3-b]pyridinyl; pyrazinyl; pyrazolyl; substituted pyrazolyl, e.g. hydroxyalkylpyrazolyl, especially 1-(2-hydroxy-ethyl)-1H-pyrazolyl or 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl; quinolinyl; 2-oxo-2,3-dihydro-1H-indol-5-yl; 1-methyl-2,3-dihydro-1H-indol-5-yl; 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl, 2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, and 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl.

In another embodiment, unsubstituted or substituted heterocyclyl is selected from pyridyl; alkylpyridyl, in particular lower-alkylpyridyl, e.g. methylpyridyl, e.g., 2-, 3- or 4-methylpyridyl, especially 2-methylpyridyl or 3-methylpyridyl; alkoxypyridyl, in particular lower-alkoxypyridyl, e.g. methoxypyridyl, e.g., 2-, 3- or 4-methoxypyridyl, especially 2-methoxypyridyl or 3-methoxypyridyl or di-methoxypyridyl, e.g. 2,3-dimethoxypyridyl, or ethoxypyridyl, e.g., 2-, 3- or 4-ethoxypyridyl especially 2-ethoxypyridyl or 3-ethoxypyridyl or di-ethoxypyridyl e.g. 2,3-diethoxypyridyl, or propyloxypyridyl, e.g., 2- or 3-propyloxypyridyl or isopropyloxypyridyl, e.g., 2- or 3-isopropyloxypyridyl; cycloalkyloxypyridyl, e.g. 2- or 3-cyclobutyloxypyridyl; cycloalkylalkoxypyridyl, e.g. cyclopropylmethoxy-pyridyl, e.g. 2 or 3-cyclopropylmethoxy-pyridyl; methoxymethylpyridyl, e.g. 2 or 3-methoxymethylpyridyl; alkoxyalkoxypyridyl, in particular methoxyethoxypyridyl, e.g. 2 or 3-methoxyethoxypyridyl; benzyloxyalkoxypyridyl, in particular benzyloxyethoxypyridyl or benzyloxypropoxypyridyl, e.g. 2-benzyloxyethoxypyridyl or 3-benzyloxypropoxypyridyl; hydroxyalkylpyridyl, e.g. 2 or 3-(2-hydroxyethyl)-pyridyl; alkyl-sulfonyl pyridyl, e.g. methanesulfonylpyridyl, especially 3-methanesulfonylpyridyl; hydroxyalkoxypyridyl, e.g. 2-(2-hydroxyethoxy)-pyridyl or 2-(3-hydroxypropoxy)-pyridyl; hydroxyalkylpyridyl, e.g. hydroxymethylpyridyl, especially 2-(hydroxymethyl)-pyridyl; alkoxycarbonylpyridyl, e.g. methoxycarbonylpyridyl, especially 2-methoxycarbonyl-pyridyl; aminopyridyl, e.g. 2- or 3-aminopyridyl; alkylaminopyridyl, in particular loweralkylaminopyridyl, e.g. 2-, 3- or 4-methylaminopyridyl, especially 2- or 3-methylaminopyridyl, 2-, 3- or 4-ethylaminopyridyl, especially 2- or 3-ethylaminopyridyl, e.g. 2- or 3-(1- or 2-propyl)aminopyridyl; dialkylaminopyridyl, in particular di-loweralkylaminopyridyl, e.g. 2-, 3- or 4-dimethylaminopyridyl, especially 2-dimethylaminopyridyl; cycloaminopyridyl, e.g. azetidinylpyridyl, especially 2-azetidin-1-yl-pyridyl or pyrrolidinylpyridyl, especially 2-pyrrolidin-2-ylpyridyl; hydroxyalkylaminopyridyl, e.g. 2-(2-hydroxyethylamino)-pyridyl; amino-haloloweralkyl-pyridyl, e.g. amino-trifluoromethyl-pyridyl, especially 2-amino-3-trifluoromethyl-pyridyl; haloalkylpyridinyl, in particular haloloweralkylpyridyl, especially, 2-, 3- or 4-trifluoromethylpyridyl, most especially 2-trifluoromethylpyridyl; halopyridyl, in particular fluoropyridyl, especially 2-fluoropyridyl; halo-alkoxy-pyridyl, e.g. fluoro-methoxy-pyridyl such as 3-fluoro-2-methoxy-pyridyl; carbamoylpyridyl, especially 2-(carbamoyl)pyridyl; alkyl-substituted carbamoyl, e.g. methylcarbamoyl, especially 2-(methylcarbamoyl)pyridyl; pyrimidinyl; loweralkylaminopyrimidinyl, e.g. 2- or 4-methylaminopyrimidinyl or 2- or 4-ethylaminopyrimidinyl; di-loweralkylaminopyrimidinyl, e.g. 2- or 4-methylethylaminopyrimidinyl, 2- or 4-dimethylaminopyrimidinyl, especially 2-dimethylaminopyrimidinyl; alkoxypyrimidinyl, in particular methoxypyrimidinyl or ethoxypyrimidinyl, e.g. 2-methoxypyrimidinyl or 2-ethoxypyrimidinyl; 1H-pyrrolo[2,3-b]pyridinyl; 1-methyl-1H-pyrrolo[2,3-b]pyridinyl; pyrazinyl; pyrazolyl; substituted pyrazolyl, e.g. hydroxyalkylpyrazolyl, especially 1-(2-hydroxy-ethyl)-1H-pyrazolyl or 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl; quinolinyl; 2-oxo-2,3-dihydro-1H-indol-5-yl; 1-methyl-2,3-dihydro-1H-indol-5-yl.

The term 5-membered heteroaryl refers to aromatic 5-membered heterocyclyl. “5-membered” meaning that there are 5 ring atoms, one or more being a heteroatom, such as nitrogen, oxygen or sulfur, and, for example includes monocyclic rings, such as thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, imidazolyl, tetrazolyl or thiadiazolyl, preferably pyrazolyl, each being unsubstituted or substituted with 1 to 3 substituents.

In an embodiment, the term 5-membered heteroaryl as defined above refers to pyrazolyl or isoxazolyl, each being unsubstituted or substituted with 1 to 3 substituents. Most preferably the 5-membered heteroaryl as defined above refers to pyrazolyl, which is unsubstituted or substituted with 1 to 3 substituents,

“Substituted”, wherever used for a moiety, means that one or more hydrogen atoms in the respective moiety, especially up to 5 hydrogen atoms, more especially up to three of the hydrogen atoms are replaced independently of each other by a corresponding number of substituents, which preferably are independently selected from the group consisting of lower alkyl, e.g., methyl, ethyl, isopropyl or propyl; halo, e.g., F, Cl, Br or I; halo-lower alkyl, e.g., fluoroalkyl, such as trifluoromethyl; hydroxy; carboxy; lower alkoxy, e.g., methoxy, ethoxy, propyloxy or isopropyloxy; aryl-lower alkyl, e.g. phenyl-lower alkyl; aryl-lower alkoxy, e.g. phenyl-lower alkoxy; lower alkanoyloxy; lower alkanoyl; hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; alkoxy lower alkyl, e.g. 2-methoxyethyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; amino; mono- or di-substituted amino; cyclic amino, e.g. aziridinyl, azetidinyl or pyrrolidinyl; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; alkylamino-lower alkandiyl; dialkylamino-lower alkandiyl; N-lower alkylamino; N,N-di-lower alkylamino; amino lower alkoxy; lower alkanoylamino; lower alkanoyl-lower alkyl-amino; benzoylamino; carbamoyl-lower alkoxy; N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy; amidino; N-hydroxy-amidino; hydroxylamine; alkoxyamino; nitro; guanidino; amidino-lower alkyl, e.g., 2-amidinoethyl; N-hydroxyamidino-lower alkyl, e.g., N-hydroxy-amidino-methyl or -2-ethyl; carboxy; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl, e.g., benzyloxycarbonyl; lower alkanoyl; sulfo; lower alkanesulfonyl, e.g., methanesulfonyl (CH₃—S(O)₂—); sulfonamide (NH₂—S(O)₂—); dioxolo; phosphono (—P(═O)(OH)₂); hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl; carbamoyl; mono- or di-lower alkylcarbamoyl; carbamoyl lower alkyl; sulfamoyl; sulfamide; mono- or di-lower alkylaminosulfonyl; lower alkanesulfonylamino; lower alkanesulfonyl-lower alkyl-amino; cyano; cyano-lower alkyl, e.g., cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; aryl (e.g., phenyl), where aryl is unsubstituted or substituted with any of the substituents defined above, and especially is phenyl which is unsubstituted or substituted with up to 4 substituents, preferably up to 2 substituents, wherein the substituents are the same or different and are independently selected from halo, (e.g., Cl or F)cyano, cyano lower alkyl, (e.g., cyanomethyl, cyanoethyl and cyanopropyl)lower alkyl, lower alkoxy, amino-lower alkyl sulfanyl, thiol-lower alkyl, amino-lower alkyl, or amino-lower alkoxy, wherein the amino group in each case can be mono- or di-substituted, e.g., —(C₁-C₇)_(m)NR₈R₉; or —O—(C₁-C₇)_(m)NR₈R₉, wherein

-   -   m is 0 or 1; and     -   R₈ and R₉ can be the same or different and are independently H;         lower alkyl, e.g., methyl, ethyl or propyl; lower cycloalkyl,         e.g., cyclopropyl, or     -   R₈ and R₉, together with the N atom, form a 3- to 8-membered         heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur         atoms, e.g., azetidinyl, pyrrolidinyl, piperidino, morpholinyl,         imidazolinyl, piperazinyl or lower alkyl-piperazinyl.

“Substituted” also includes amino-carbonyl-lower alkyl, e.g., R₈R₉N—C(O)—CH₂—, wherein R₈ and R₉ are as defined above. “Substituted” also includes heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkoxy or heterocyclyl-lower alkanesulfanyl, wherein the heterocyclyl in each case is a substituted or unsubstituted 3- to 8-membered heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur atoms, e.g., imidazolyl, imidazolinyl, pyrrolidinyl, morpholinyl, azetidinyl, pyridyl, pyrazolyl, piperidino, piperidyl, piperazinyl or lower alkyl-piperazinyl. “Substituted” also includes C₃-C₁₀cycloalkyl, e.g., cyclopropyl or cyclohexyl; hydroxyC₃-C₈cycloalkyl, e.g., hydroxy-cyclohexyl; heteroaryl with 4 or 6 ring atoms and 1-4 ring heteroatoms selected from O, N and S, especially furyl, 1,4 oxazinyl, or pyridyl. “Substituted” also includes —NR₈R₉, wherein R₈ and R₉ can be the same or different and are independently H; lower alkyl, e.g., methyl, ethyl or propyl; lower cycloalkyl, e.g., cyclopropyl; or the R₈ and R₉ can, with the N atom, form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur atoms, e.g., azetidinyl, pyrrolidinyl, piperidino, morpholinyl, imidazolinyl, piperazinyl or lower alkyl-piperazinyl.

In an embodiment, the present invention provides compounds of the formula (I)

wherein

-   -   X is O or S;     -   Y is CH or N;     -   R¹ is a substituted or unsubstituted 5-membered heteroaryl;     -   R² is hydrogen or lower alkyl;     -   R³ is a substituted or unsubstituted aryl or heterocyclyl; and     -   R⁴, R⁵ and R⁶ are hydrogen;         or a pharmaceutically acceptable salt, solvate, hydrate or         prodrug thereof.

For the avoidance of doubt, substituents are only bound at positions where chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort, which substitutions are possible and which are not. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated, e.g., olefinic, bonds.

The terms “treatment” or “therapy” refer to the prophylactic or preferably therapeutic including, but not limited to, palliative, curing, symptom-alleviating, symptom-reducing, kinase-regulating and/or kinase-inhibiting, treatment of said diseases, especially of the diseases mentioned below.

Where subsequently or above the term “use” is mentioned (as verb or noun) (relating to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof), this includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of a protein or lipid kinase dependant disease and in particular PI3K dependent disease, the use for the manufacture of pharmaceutical compositions for use in the treatment of a protein or lipid kinase dependant disease and in particular PI3K dependent disease, methods of use of one or more compounds of the formula (I) in the treatment of a protein or lipid kinase dependant disease and in particular PI3K dependent disease, the use of pharmaceutical preparations comprising one or more compounds of the formula (I) for the treatment of a protein or lipid kinase dependent disease, and one or more compounds of the formula (I) for use in the treatment of a protein or lipid kinase dependent disease, as appropriate and expedient and if not stated otherwise. In particular, diseases to be treated and are thus preferred for “use” of a compound of formula (I) are selected from protein or lipid kinase dependent (“dependent” meaning also “supported”, not only “solely dependent”) diseases mentioned herein, especially proliferative diseases mentioned herein, more especially any one or more of these or other diseases that depend on one or more of protein or lipid kinases such as PI4K (phosphatidylinositol 4-kinase) and/or PI3 kinases (phosphatidylinositol 3-kinase), for example, inhibition of the PI3K superfamily which comprises PI3Kalpha, PI3 Kbeta, PI3 Kdelta, PI3 Kgamma and mTOR, or one or more of the individual kinase members thereof, including Vps34 (class III PI3K), PI3-kinase-related protein kinase family (PIKK, class IV PI3K) which includes DNA-PK, ATM, ATR, hSMG-1 and mTOR, or any combinations of two or more of these, or a mutant of any one or more of these, and a compound of the formula (I) can therefore be used in the treatment of a lipid or protein kinase dependent disease, especially a disease depending on one or more of the kinases mentioned above and below, where (especially in the case of aberrantly highly-expressed, constitutively activated and/or mutated kinases or defective dephosphorylation of their substrate(s)) said kinase-dependent disease is dependent on the activity of one or more of the said kinases or the pathways in which they are involved.

The compounds of formula (I) have valuable pharmacological properties and are useful in the treatment of lipid and/or protein kinase dependent diseases, e.g., as drugs to treat proliferative diseases.

In the following detailed description and embodiments, which are to be taken independently, collectively or in any combination or sub-combination, the invention relates to a compound of the formula (I), in e.g. free base form or in acid addition salt form, wherein the substituents are as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

With respect to formula (I), the following detailed description is provided.

R¹

As indicated hereinabove, R¹ is a 5-membered heteroaryl having the appropriate corresponding meaning as for heteroaryl given above, with “5-membered” meaning that there are 5 ring atoms, one or more being a heteroatom, such as nitrogen, oxygen or sulfur. Such 5-membered heteroaryl groups include monocyclic rings, such as pyrazolyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, imidazolyl, tetrazolyl or thiadiazolyl, preferably pyrazolyl, each being unsubstituted or substituted, e.g. by the groups listed herein under “substituted”.

In an embodiment, R¹ is pyrazolyl or isoxazolyl, each being unsubstituted or substituted, e.g. by the groups listed herein under “substituted”.

In an embodiment, R¹ is unsubstituted or substituted pyrazolyl or unsubstituted or substituted isoxazolyl. Preferably the pyrazolyl is substituted, preferably by one, two or three substituents and the isoxazolyl is substituted, preferably by one or two substituents, wherein in each case, said substituents may for example be independently selected from halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted lower alkoxy, unsubstituted or substituted lower alkylamino, unsubstituted or substituted alkoxy lower alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted carbamoyl lower alkyl, lower mono- and di-alkyl carbamoyl lower alkyl, unsubstituted or substituted cycloaminocarbonyl lower alkyl, unsubstituted or substituted heterocyclylcarbonyl lower alkyl, unsubstituted or substituted hydroxyl lower alkyl, unsubstituted or substituted carboxy lower alkyl, halo-loweralkyl, hydroxycarbonyl-loweralkyl, morpholinecarbonylalkyl, hydroxy or amino.

In an embodiment, R¹ is unsubstituted isoxazolyl.

In an embodiment, R¹ is isoxazolyl substituted by one or two substituents selected from halo, lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted lower alkoxy, substituted or unsubstituted lower alkyl amino, hydroxy or amino. In an embodiment, R¹ is isoxazolyl substituted by one or two substituents selected from halo, unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower alkynyl, unsubstituted or substituted cycloalkyl, hydroxy or amino.

In an embodiment, R¹ is isoxazolyl substituted by one or two substituents selected from unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted alkynyl, unsubstituted cycloloweralkyl, hydroxy or amino.

In an embodiment, R¹ is isoxazolyl substituted by one or two, same or different, unsubstituted lower alkyl substituents (in particular C₁-C₄alkyl) such as methyl or ethyl, preferably methyl.

In an embodiment, when R¹ is unsubstituted or substituted isoxazolyl, said isoxazolyl is isoxazol-3-yl, isoxazol-4-yl or isoxazol-5-yl.

It is preferred that a substituent of said substituted isoxazolyl is bonded to the isoxazolyl ring at the alpha position to the ring atom which bonds the isoxazolyl ring to the rest of the molecule (that is, the alpha position is at a position on the isoxazolyl ring which is next to the isoxazolyl ring atom which is bonded to the imidazoquinolinone part of the molecule). The isoxazolyl ring atom which is bonded to the rest of the molecule (i.e. the imidazoquinolinone part) is a carbon atom. Thus, preferred isoxazolyl groups are alpha-substituted isoxazolyl. For the avoidance of doubt the ring atom at the alpha position may be a carbon, nitrogen or oxygen ring atom, with at least one atom in the alpha position being a carbon atom, but, for chemical valency reasons, only an alpha carbon atom may be substituted.

An embodiment of the invention includes compounds of formula (I) wherein R¹ is unsubstituted or substituted isoxazol-4-yl, thus R¹ in this embodiment is represented by a group of formula (AB):

wherein, the curved line indicates the bonding position to the rest of the molecule and the alpha position is shown by the atoms labeled with a * symbol, and

R¹⁶ and R¹⁷ are independently selected from hydrogen, halo, unsubstituted or substituted lower alkyl (especially C₁-C₄alkyl), unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower alkynyl, unsubstituted or substituted lower alkoxy, unsubstituted or substituted lower alkylamino, unsubstituted or substituted cycloalkyl or unsubstituted or substituted cycloalkenyl.

In an embodiment, R¹⁶ and R¹⁷ are independently selected from hydrogen, halo or unsubstituted or substituted lower alkyl (especially C₁-C₄alkyl) such as methyl or ethyl.

In an embodiment, R¹⁶ and R¹⁷ are independently selected from hydrogen, methyl or ethyl.

In an embodiment, at least one of R¹⁶ and R¹⁷ is not hydrogen.

In an embodiment of the present invention, R¹ is of formula (AB) shown above; and

-   -   R¹⁶ is C₁-C₄alkyl (especially methyl or ethyl); and     -   R¹⁷ is C₁-C₄alkyl (especially methyl or ethyl);

In a specific embodiment of the present invention, R¹ is of formula (AB) shown above; and

R¹⁶ and R⁷⁷ are each methyl.

Preferably R¹ is unsubstituted or substituted pyrazolyl. Preferably the pyrazolyl is substituted, preferably by one, two or three substituents, wherein said substituents may for example be independently selected from halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted lower alkoxy, unsubstituted or substituted lower alkylamino, unsubstituted or substituted alkoxy lower alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted carbamoyl lower alkyl, lower mono- and di-alkyl carbamoyl lower alkyl, unsubstituted or substituted cycloaminocarbonyl lower alkyl, unsubstituted or substituted heterocyclylcarbonyl lower alkyl, unsubstituted or substituted hydroxyl lower alkyl, unsubstituted or substituted carboxy lower alkyl, halo-loweralkyl, hydroxycarbonyl-loweralkyl, morpholinecarbonylalkyl, hydroxy or amino.

Preferred substituents are selected from the group consisting of halo, lower alkyl, lower alkenyl, lower alkynyl, cycloloweralkyl, hydroxy, amino, halo lower alkyl, 2-hydroxyethyl, methoxyethyl, hydroxycarbonylmethyl (HOC(O)CH₂—), dialkylaminocarbonylmethyl e.g. dimethylaminocarbonylmethyl (Me₂NC(O)CH₂—) or ethylmethylaminocarbonylmethyl (EtMeNC(O)CH₂—), (methoxyethyl)(methyl)aminocarbonylmethyl ((MeOEt)(Me)NC(O)CH₂—), azetidinylcarbonylmethyl e.g. 2-azetidin-1-yl-2-oxo-ethyl, morpholinecarbonylmethyl, (4-methylpiperazin-1yl)carbonylmethyl.

It is preferred that the substituent (if mono-substituted) or at least one of the substituents (if two or three substituents are present) is bonded to the pyrazole ring at the alpha position to the ring atom which bonds the pyrazole ring to the rest of the molecule (that is, the alpha position is at a position on the pyrazole ring which is next to the pyrazole ring atom which is bonded to the imidazoquinolinone part of the molecule). The pyrazole ring atom which is bonded to the rest of the molecule (i.e. the imidazoquinolinone part) is preferably a carbon atom. Thus, preferred pyrazolyl groups are alpha-substituted pyrazolyl. For the avoidance of doubt the ring atom at the alpha position may be a carbon or nitrogen ring atom. Thus an embodiment of the invention includes compounds of formula (I) wherein R¹ is a group selected from:

wherein, the curved line indicates the bonding position to the rest of the molecule and the alpha position is shown by the atoms labeled with a * symbol, and

R¹⁰ is independently selected from hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted lower alkoxy, substituted or unsubstituted lower alkyl amino, hydroxy or amino.

Preferably, R¹⁰ is independently selected from hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower alkynyl, unsubstituted or substituted cycloalkyl, hydroxy or amino.

More preferably, R¹⁰ is independently selected from hydrogen, unsubstituted lower alkyl, unsubstituted lower alkenyl, unsubstituted alkynyl, unsubstituted cycloloweralkyl, hydroxy or amino.

More preferably, R¹⁰ is independently selected from hydrogen or lower alkyl such as methyl or ethyl.

R¹¹ is independently selected from hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted lower alkoxy, unsubstituted or substituted lower alkylamino, unsubstituted or substituted alkoxy lower alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted cycloalkenyl; unsubstituted or substituted carbamoyl lower alkyl; lower mono- and di-alkyl carbamoyl lower alkyl; unsubstituted or substituted cycloaminocarbonyl lower alkyl; unsubstituted or substituted heterocyclylcarbonyl lower alkyl.

More preferably R¹¹ is independently selected from hydrogen, unsubstituted or substituted lower alkyl such as methyl, ethyl, propyl, isopropyl; halo lower alkyl such as trifluoromethyl; hydroxyl lower alkyl such as hydroxyl ethyl; alkoxy lower alkyl such as methoxyethyl; carbamoyl lower alkyl such as carbamoylmethyl; lower mono- or di-alkyl carbamoyl lower alkyl such as methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, ethylmethylcarbamoylmethyl or diethylcarbamoylmethyl; cycloaminocarbonyl lower alkyl such as azetidinylcarbonylmethyl; or carboxy lower alkyl such as carboxymethyl.

More preferably R¹¹ is independently selected from hydrogen, lower alkyl such as methyl, ethyl, propyl, isopropyl or halo lower alkyl such as trifluoromethyl.

More preferably, R¹¹ is independently selected from hydrogen, methyl, ethyl or trifluoromethyl.

R¹⁴ is independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted hydroxyl lower alkyl, unsubstituted or substituted lower alkoxy, unsubstituted or substituted lower alkylamino, unsubstituted or substituted alkoxy lower alkyl, unsubstituted or substituted cycloalkyl; unsubstituted or substituted cycloalkenyl; unsubstituted or substituted carbamoyl lower alkyl; lower mono- or di-alkyl carbamoyl lower alkyl; unsubstituted or substituted cycloaminocarbonyl lower alkyl; unsubstituted or substituted heterocyclylcarbonyl lower alkyl; unsubstituted or substituted carboxy lower alkyl.

More preferably R¹⁴ is independently selected from hydrogen or unsubstituted or substituted lower alkyl such as unsubstituted or substituted hydroxyl lower alkyl; unsubstituted or substituted alkoxy lower alkyl; unsubstituted or substituted carbamoyl lower alkyl; lower mono- or di-alkyl carbamoyl lower alkyl; unsubstituted or substituted cycloaminocarbonyl lower alkyl; unsubstituted or substituted heterocyclylcarbonyl lower alkyl; unsubstituted or substituted carboxy lower alkyl.

More preferably R¹⁴ is independently selected from hydrogen; unsubstituted lower alkyl such as methyl, ethyl, propyl or isopropyl; hydroxyl lower alkyl such as hydroxyl ethyl; alkoxy lower alkyl such as methoxyethyl; carbamoyl lower alkyl such as carbamoylmethyl; lower mono- or di-alkyl carbamoyl lower alkyl such as methylcarbamoylmethyl, ethylcarbamoylmethyl, dimethylcarbamoylmethyl, ethylmethylcarbamoylmethyl; diethylcarbamoylmethyl or (methoxyethyl)(methyl)carbamoylmethyl; cycloaminocarbonyl lower alkyl such as azetidinylcarbonylmethyl; unsubstituted or substituted heterocyclylcarbonyl lower alkyl such as morpholinecarbonyl lower alkyl or piperazinecarbonyl lower alkyl; or carboxy lower alkyl such as carboxymethyl;

More, preferably R¹⁴ is independently selected from hydrogen; unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted haloC₁-C₄alkyl, 2-hydroxyethyl, methoxyethyl, hydroxycarbonylmethyl (HOC(O)CH₂—), dialkylaminocarbonylmethyl e.g. dimethylaminocarbonylmethyl (Me₂NC(O)CH₂—) or ethylmethylaminocarbonylmethyl (EtMeNC(O)CH₂—), (methoxyethyl)(methyl)aminocarbonylmethylmethyl ((MeOEt)(Me)NC(O)CH₂—), azetidinylcarbonylmethyl e.g. 2-azetidin-1-yl-2-oxo-ethyl, morpholinecarbonylmethyl e.g. 4-morpholinecarbonylmethyl, (4-methylpiperazin-1yl)carbonylmethyl.

Most preferably R¹⁴ is independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, 2-hydroxyethyl, methoxyethyl, hydroxycarbonylmethyl (HOC(O)CH₂—), dimethylaminocarbonylmethyl (Me₂NC(O)CH₂—), ethylmethylaminocarbonylmethyl (EtMeNC(O)CH₂—), (methoxyethyl)(methyl)aminocarbonylmethylmethyl ((MeOEt)(Me)NC(O)CH₂—), 2-azetidin-1-yl-2-oxo-ethyl, 4-morpholinecarbonylmethyl and (4-methylpiperazin-1yl)carbonylmethyl.

R¹², R¹³ and R¹⁵ are independently selected from hydrogen, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted lower alkoxy, unsubstituted or substituted lower alkylamino, unsubstituted or substituted cycloalkyl or unsubstituted or substituted cycloalkenyl.

More preferably R¹², R¹³ and R¹⁵ are independently selected from hydrogen, halo such as fluoro, chloro, bromo, or unsubstituted or substituted lower alkyl such as methyl or ethyl.

More preferably R¹², R¹³ and R¹⁵ are independently selected from hydrogen, chloro, methyl or ethyl.

Preferably, one of R¹⁰ and R¹² is not hydrogen.

Preferably, at least one of R¹³ and R¹⁵ is not hydrogen.

In an embodiment of the present invention, R₁ is of formula (A) or (B) shown above; and

-   -   R¹⁰ is C₁-C₄alkyl (especially methyl or ethyl);     -   R¹¹ is hydrogen or C₁-C₄alkyl (especially methyl) or         fluoroC₁-C₄alkyl (especially trifluoromethyl); and     -   R¹² is hydrogen or C₁-C₄alkyl (especially methyl);     -   R¹³ is hydrogen or C₁-C₄alkyl (especially methyl);     -   R¹⁴ is C₁-C₄alkyl (especially methyl, ethyl or isopropyl),         2-hydroxyethyl, methoxyethyl, hydroxycarbonylmethyl         (HOC(O)CH₂—), dimethylaminocarbonylmethyl (Me₂NC(O)CH₂—),         diethylaminocarbonylmethyl (Et₂NC(O)CH₂—),         ethylmethylaminocarbonylmethyl (EtMeNC(O)CH₂—),         (methoxyethyl)(methyl)aminocarbonylmethylmethyl         ((MeOEt)(Me)NC(O)CH₂—), 4-morpholinecarbonylmethyl,         (4-methylpiperazin-1yl)carbonylmethyl,         2-azetidin-1-yl-2-oxo-ethyl; and     -   R¹⁵ is methyl or chloro.

In another embodiment of the present invention, R₁ is of formula (A) shown above; and

-   -   R¹⁰ is C₁-C₄alkyl (especially methyl or ethyl);     -   R¹¹ is hydrogen or C₁-C₄alkyl (especially methyl) or         fluoroC₁-C₄alkyl (especially trifluoromethyl); and     -   R¹² is hydrogen or C₁-C₄alkyl (especially methyl).

In another embodiment of the present invention, R₁ is of formula (B) shown above; and

-   -   R¹³ is hydrogen or C₁-C₄alkyl (especially methyl);     -   R¹⁴ is C₁-C₄alkyl (especially methyl, ethyl or isopropyl),         2-hydroxyethyl, methoxyethyl, hydroxycarbonylmethyl         (HOC(O)CH₂—), dimethylaminocarbonylmethyl (Me₂NC(O)CH₂—),         ethylmethylaminocarbonylmethyl (EtMeNC(O)CH₂—),         (methoxyethyl)(methyl)aminocarbonylmethylmethyl         ((MeOEt)(Me)NC(O)CH₂—), 2-azetidin-1-yl-2-oxo-ethyl,         4-morpholinecarbonylmethyl and         (4-methylpiperazin-1yl)carbonylmethyl; and     -   R¹⁵ is methyl or chloro.

In an embodiment, R¹ is selected from 1,5-dimethyl-1H-pyrazol-4-yl, 2-ethyl-2H-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 2,5-dimethyl-2H-pyrazol-3-yl, 1-isopropyl-3-methyl-1H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl, 2,4-dimethyl-2H-pyrazol-3-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl, 1-hydroxycarbonyl methyl-3-methyl-pyrazol-4-yl, 1-dimethylaminocarbonylmethyl-3-methyl-pyrazol-4-yl, 1-dimethylaminocarbonylmethyl-3,5-dimethyl-pyrazol-4-yl, 1-diethylaminocarbonylmethyl-3-methyl-pyrazol-4-yl, 1-(2-hydroxyethyl)-3-methyl-pyrazol-4-yl, 1-(2-azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl, 1-(4-morpholin)-carbonylmethyl-3-methyl-pyrazol-4-yl, 3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl, 1-methyl-3-chloro-pyrazol-4-yl, 1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl, 1-N-ethyl-N-methylaminocarbonylmethyl-3-methyl-pyrazol-4-yl or 3,5-dimethyl-isoxazol-4-yl.

In another embodiment R¹ is selected from 1,5-dimethyl-1H-pyrazol-4-yl, 2-ethyl-2H-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 2,5-dim ethyl-2H-pyrazol-3-yl, 1-isopropyl-3-methyl-1H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl, 2,4-dimethyl-2H-pyrazol-3-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl, 1-hydroxycarbonylmethyl-3-methyl-pyrazol-4-yl, 1-dimethylaminocarbonylmethyl-3-methyl-pyrazol-4-yl, 1-dimethylaminocarbonylmethyl-3,5-dimethyl-pyrazol-4-yl, 1-diethylaminocarbonylmethyl-3-methyl-pyrazol-4-yl, 1-(2-hydroxyethyl)-3-methyl-pyrazol-4-yl, 1-(2-azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl, 1-(4-morpholin)-carbonylmethyl-3-methyl-pyrazol-4-yl, 1-methyl-3-chloro-pyrazol-4-yl, 1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl.

R²

In an embodiment, R² is preferably selected from hydrogen, C₁-C₄alkyl or C₁-C₄alkenyl. In particular R² is selected from hydrogen, methyl, ethyl and propenyl (especially propen-3-yl).

In another embodiment, R² is preferably selected from hydrogen or C₁-C₄alkyl. Most preferably R² is selected from hydrogen, methyl and ethyl.

R³

R³ is unsubstituted or substituted aryl or unsubstituted or substituted heterocycyl as defined herein above, each of which, when substituted, is substituted by one or more, especially 1-3, substituents independently selected from the group consisting of the substituents defined under “substituted”.

When R³ is unsubstituted or substituted aryl, it is preferably C₆-C₁₀aryl which is unsubstituted, or substituted by one or more, especially 1-3, substituents independently selected from the group consisting of the substituents defined under “substituted”.

When R³ is an aryl group, (especially C₆-C₁₀aryl, more especially phenyl) it is unsubstituted, or substituted by one or more, especially 1-3, substituents independently selected from the group consisting of the substituents defined under “substituted”.

When the R³ group is an aryl group, (especially C₆-C₁₀aryl, more especially phenyl) when substituted, the substituents may be selected from the group consisting of halo, especially fluoro, chloro, bromo or iodo, in particular fluoro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino; mono or disubstituted amino, especially alkyl-substituted amino or hydroxyalkyl-substituted amino, e.g. dimethyl amino or 2-hydroxyethyl amino; cyclic amino, such as aziridinyl or azetidinyl; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; lower alkoxy, e.g., methoxy, ethoxy or propoxy (e.g. iso-propoxy); hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl or 3-cyanopropyl; amidino; N-hydroxyamidino; hydroxyamino; alkoxyamino; nitro; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; substituted phenyl or (especially 1- or 2-)naphthyl; sulfonyl; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide (or lower alkylaminosulfonyl or N,N-di-loweralkyl aminosulfonyl, e.g. methylaminosulfonyl or dimethylaminosulfonyl) or pyrrolidine-1-sulfonyl; lower alkyl sulfonyl amino, e.g. methylsulfonylamino; lower alkyl sulfonylalkandiylamino, e.g. methylsulfonylmethylamino; lower alkylsulfonyl-N-lower alkylamino, e.g. methylsulfonyl-N-methylamino; [1,3]dioxolo; substituted [1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl; substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl; heterocycle, e.g. pyrazol; heterocyclyl lower alkyl; heteroaryl or heteroaryl lower alkyl.

In an embodiment, when the R³ group is an aryl group, (especially C₆-C₁₀aryl, more especially phenyl) when substituted, the substituents may be selected from the group consisting of halo, especially fluoro, chloro, bromo or iodo, in particular fluoro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino; mono or disubstituted amino, especially alkyl-substituted amino or hydroxyalkyl-substituted amino, e.g. dimethyl amino or 2-hydroxyethyl amino; cyclic amino, such as aziridinyl or azetidinyl; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; lower alkoxy, e.g., methoxy or ethoxy; hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl or 3-cyanopropyl; amidino; N-hydroxyamidino; hydroxyamino; alkoxyamino; nitro; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; substituted phenyl or (especially 1- or 2-)naphthyl; sulfonyl; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide or pyrrolidine-1-sulfonyl; [1,3]dioxolo; substituted[1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl; substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl; heterocycle, e.g. pyrazol; heterocyclyl lower alkyl; heteroaryl or heteroaryl lower alkyl.

In an embodiment, unsubstituted or substituted aryl for R³ is selected from phenyl; hydroxyphenyl, e.g., 2-, 3- or 4-hydroxyphenyl; methoxyphenyl, e.g., 2-, 3- or 4-methoxyphenyl or 3,4-dimethoxyphenyl; ethoxyphenyl, e.g., 2-, 3- or 4-ethoxyphenyl or 3,4-diethoxyphenyl; propoxyphenyl (e.g. iso-propoxyphenyl) such as 3-propoxyphenyl (e.g. 3-iso-propoxyphenyl); methoxy ethoxy-phenyl, e.g. 3-methoxy-4-ethoxy phenyl or 4-methoxy-3-ethoxy phenyl, other lower-alkoxy phenyl, e.g. 3-methoxy-4-(2-methoxy ethoxy)-phenyl, halo-alkoxy-phenyl, e.g. fluoro-(iso-propoxy)-phenyl, e.g. 2-fluoro-3-(iso-propoxy)-phenyl; hydroxy alkoxy phenyl, e.g. 3-methoxy-4-hydroxy phenyl; halo-hydroxy-phenyl, e.g. fluoro-hydroxy-phenyl such as 3-fluoro-5-hydroxy-phenyl; hydroxy-haloalkyl-phenyl, e.g. hydroxy-fluoroalkyl-phenyl such as 3-hydroxy-5-trifluoromethyl-phenyl; 2,2-difluoro-benzo[1,3]dioxolo; benzene sulfonamide, e.g. N-methylbenzenesulfonamide and N,N-dimethylbenzenesulfonamide; 3-(pyrrolidine-1-sulfonyl)-phenyl, N-(phen-3-yl)-methanesulfonamide or N-methyl-N-phen-3-yl-methanesulfonamide; alkyl-sulfonyl phenyl, e.g. 3-methanesulfonylphenyl; benzamide e.g. 2-, 3- or 4-benzamide, 2-, 3- or 4-N-methyl-benzamide or 2-, 3- or 4-N,N-dimethyl-benzamide; pyrazol-phenyl, e.g. 4-(pyrazol)-phenyl or alternatively (1H-pyrazol-1yl)-phenyl, in particular 4-(1H-pyrazol-1yl)-phenyl; imidazol-phenyl, especially (1H-imidazol-2-yl)phenyl, in particular 4-(1H-imidazol-2-yl)phenyl.

In an embodiment, unsubstituted or substituted aryl for R³ is selected from phenyl; hydroxyphenyl, e.g., 2-, 3- or 4-hydroxyphenyl; methoxyphenyl, e.g., 2-, 3- or 4-methoxyphenyl or 3,4-dimethoxyphenyl; ethoxyphenyl, e.g., 2-, 3- or 4-ethoxyphenyl or 3,4-diethoxyphenyl; methoxy ethoxy-phenyl, e.g. 3-methoxy-4-ethoxy phenyl or 4-methoxy-3-ethoxy phenyl, other lower-alkoxy phenyl, e.g. 3-methoxy-4-(2-methoxy ethoxy)-phenyl, hydroxy alkoxy phenyl, e.g. 3-methoxy-4-hydroxy phenyl; halo-hydroxy-phenyl, e.g. fluoro-hydroxy-phenyl such as 3-fluoro-5-hydroxy-phenyl; hydroxy-haloalkyl-phenyl, e.g. hydroxy-fluoroalkyl-phenyl such as 3-hydroxy-5-trifluoromethyl-phenyl; 2,2-difluoro-benzo[1,3]dioxolo; benzene sulfonamide, e.g. N-methylbenzenesulfonamide; 3-(pyrrolidine-1-sulfonyl)-phenyl, N-(phen-3-yl)-methanesulfonamide or N-methyl-N-phen-3-yl-methanesulfonamide; alkyl-sulfonyl phenyl, e.g. 3-methanesulfonylphenyl; benzamide e.g. 2-, 3- or 4-benzamide, 2-, 3- or 4-N-methyl-benzamide or 2-, 3- or 4-N,N-dimethyl-benzamide; pyrazol-phenyl, e.g. 4-(pyrazol)-phenyl or alternatively (1H-pyrazol-1yl)-phenyl, in particular 4-(1H-pyrazol-1yl)-phenyl; imidazol-phenyl, especially (1H-imidazol-2-yl)phenyl, in particular 4-(1H-imidazol-2-yl)phenyl.

When the R³ group is a heterocyclyl or preferably heteroaryl, said heterocyclyl or heteroaryl may be selected from the group consisting of indolyl, 2,3-dihydro-1H-indol-5-yl, 1-methyl-2,3-dihydro-1H-indol-5-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyridyl, pyrimidinyl (especially pyrimidin-5-yl), 1H-pyrrolo[2,3-b]pyridin-5-yl, 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazolyl, pyrazol-4-yl, pyrazinyl, quinolyl, quinol-3-yl, 1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl each of these heterocycle radicals being unsubstituted or substituted by one or two radicals selected from the substituents described under “substituted”, in particular from the group consisting of halo, especially fluoro, chloro, bromo or iodo, more especially fluoro or chloro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino, mono or disubstituted amino, especially alkyl-substituted amino or hydroxyalkyl-substituted amino, e.g. dimethyl amino or 2-hydroxyethyl amino; cyclic amino, such as aziridinyl or azetidinyl; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; lower alkoxy, e.g., methoxy or ethoxy; lower alkoxy lower alkyl, e.g. 2-methoxyethyl; hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl and 3-cyanopropyl; amidino; N-hydroxyamidino; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; substituted phenyl or (especially 1- or 2-) naphthyl; sulfonyl; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide or pyrrolidine-1-sulfonyl; [1,3]dioxolo; substituted [1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl; substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl; aminocarbonylalkyl, such as aminocarbonyl loweralkyl, e.g. aminocarbonylmethyl; N-mono-substituted aminocarbonylalkyl, such as N-loweralkyl aminocarbonyl loweralkyl, e.g. methylaminocarbonylmethyl; N-di-substituted aminocarbonylalkyl, such as N-di-loweralkyl aminocarbonyl loweralkyl, e.g. dimethylaminocarbonylmethyl, or other N-di-substituted aminocarbonylalkyl, such as 4-morpholinecarbonylmethyl. The heterocycle group may also be substituted with another heterocycle, e.g. 3H-tetrazolyl (in particular 3H-tetrazol-5-yl), pyrazol, heterocyclyl lower alkyl, heteroaryl or heteroaryl lower alkyl as defined herein.

Very preferred heterocyclic groups, which may be substituted or unsubstituted, include indolyl, 1-methyl-2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, pyrazolyl, pyrazinyl, quinolyl, 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl, 2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl and 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl each of these heterocycle radicals being unsubstituted or substituted by one to two radicals selected from the substituents described under “substituted”, in particular from the group consisting of halo, especially fluoro, chloro, bromo or iodo, more especially fluoro or chloro, in particular fluoro; halo-lower alkyl, especially fluoroalkyl, in particular trifluoromethyl; hydroxyl; amino, mono or disubstituted amino, especially alkyl-substituted amino, hydroxyalkyl-substituted amino or alkoxyalkyl-substituted amino, e.g. dimethyl amino, 2-hydroxyethyl amino or 2-methoxyethyl amino; cyclic amino, such as aziridinyl, azetidinyl or pyrrolidinyl; substituted cyclic amino, e.g. hydroxy cyclic amino; amino-lower alkyl, e.g., aminomethyl, 2-aminoethyl or 3-aminopropyl; alkylamino-lower alkyl, e.g. methylaminomethyl, ethylaminomethyl, methylaminoethyl or ethylaminoethyl; dialkylamino-loweralkyl, e.g. dimethylaminomethyl, dimethylaminoethyl, methylethylaminomethyl, methylethylaminoethyl, diethylaminomethyl or diethylaminoethyl; cycloalkylaminoalkyl, e.g. cyclopropylaminomethyl, cyclopropylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclopentylaminomethyl or cyclopentylaminoethyl; dicycloalkylaminoalkyl, e.g. dicyclopropylaminomethyl, dicyclopropylaminoethyl, cyclopropylcyclobutylaminomethyl or cyclopropylcyclobutylaminoethyl; alkylcycloalkylaminoalkyl, e.g. cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclopropylethylaminomethyl or cyclopropylethylaminoethyl; lower alkoxy, e.g., methoxy, ethoxy or propyloxy; cycloalkoxy, e.g. cyclobutoxy; lower-alkoxyalkyl, e.g. methoxymethyl, methoxypropyl, ethoxypropyl; hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxyethyl; hydroxy lower cycloalkyl, e.g. hydroxy cyclopentyl; hydroxy lower alkoxy, e.g. hydroxyethoxy; alkoxy lower alkoxy, e.g. methoxyethoxy or ethoxyethoxy; lower alkyl, e.g., methyl, ethyl or iso-propyl; cyano; cyano-lower alkyl, e.g., 2-cyanoethyl, 2-cyanopropyl, 2-cyano-2-methylpropyl or 3-cyanopropyl; cyano lower cycloalkyl, e.g cyano cyclobutyl; amidino; N-hydroxyamidino; amidino-lower alkyl, e.g., 2-amidino-ethyl; or N-hydroxyamidino-lower alkyl, e.g., 2-(N-hydroxyamidino)-ethyl; nitro; carboxylic acid; substituted sulfonyl, e.g. alkyl-substituted sulfonyl, such as methanesulfonyl; sulfonamide, e.g. N-methylsulfonamide or pyrrolidine-1-sulfonyl; alkylsulfonylamino, e.g. methylsulfonylamino; alkylsulfonylalkylamino, e.g. methylsulfonylmethylamino; acylamino (also termed alkyl carbonyl amino), e.g. acetylamino; acyl alkyl amino, e.g. acetyl methyl amino; alkylcarbonylaminoalkyl, e.g. methylcarbonylaminomethyl; alkylaminocarbonylalkyl e.g. methylaminocarbonylmethyl; alkylcarbonyl-N-alkylamino, e.g. methylcarbonyl-N-methylamino; [1,3]dioxolo; substituted[1,3]dioxolo, e.g. 2,2-difluoro-[1,3]dioxolo; alkoxy carbonyl, such as lower alkoxy carbonyl, e.g. methoxycarbonyl; carbamoyl (also termed aminocarbonyl); substituted carbamoyl, such as alkyl-substituted carbamoyl, e.g. methylcarbamoyl, ethyl carbamoyl, iso-propyl carbamoyl or alkoxyalkyl-substituted carbamoyl (also termed alkoxyalkylaminocarbonyl), e.g. 2-methoxyethylcarbamoyl. The heterocycle group may also be substituted with another substituted or unsubstituted heterocycle, preferably a 4-7 membered ring, e.g. 1H-tetrazolyl (in particular 1H-tetrazol-5-yl), pyrazol, imidazole, triazole, azetidinyl, pyrrolidinyl, piperazinyl, methylpiperazinyl, ethylpiperazinyl, triazolonyl, methylimidazolyl or morpholino. The heterocycle group may also be substituted with heterocyclyl lower alkyl, heteroaryl or heteroaryl lower alkyl as defined herein.

In an embodiment, R³ is heterocycyl. In another embodiment, R³ is heterocycyl which is heteroaryl. In an embodiment, said heterocycyl or heteroaryl is a monocyclic 6 membered ring wherein one or two ring heteroatoms are nitrogen atoms. In a preferred embodiment, R³ is a monocyclic 6 membered heteroaryl wherein one or two ring heteroatoms are nitrogen atoms. In an embodiment, R³ is pyridyl, pyrimidinyl or pyrazinyl, each independently being unsubstituted or substituted. In an embodiment, R³ is pyridyl or pyrimidinyl, each independently being unsubstituted or substituted. In an embodiment, R³ is unsubstituted or substituted pyridyl (especially pyrid-3-yl or pyridyl-5-yl). In another embodiment R³ is unsubstituted or substituted pyrimidinyl (especially pyrimidin-5-yl).

In an embodiment, said pyrimidinyl (especially pyrimidin-5-yl) is unsubstituted or substituted, preferably substituted. When substituted, said pyrimidinyl is preferably substituted in the 2-, 4- or 2- and 4-positions on the pyrimidine ring. Typically, when mono-substituted, the pyrimidine ring is substituted in the 2-position, and when di-substituted, in the 2- and 4-positions.

When substituted, said pyrimidinyl is substituted by one or two substituents independently selected from:

di-loweralkylamino, di-alkoxy, alkylamino, alkoxy, cycloamino.

In an embodiment, heterocyclyl or heteroaryl for R³ is pyridyl, especially pyrid-3-yl or pyrid-5-yl—both of these terms mean that the pyridine ring is bonded to the rest of the imidazoquinolinone part of the molecule of formula (I) at a pyridine carbon atom which is arrived at by counting 3 atoms or 5 atoms round the pyridine ring, starting at the nitrogen atom of the pyridine ring, which counts as 1. In an embodiment, said pyridyl (preferably pyrid-3-yl or pyrid-5-yl) is unsubstituted or substituted, preferably substituted. When substituted, said pyridinyl is preferably substituted in the 5-, 6-, or 5- and 6-position positions of the pyridine ring (with reference to pyridin-3-yl),

When substituted, said pyridyl is substituted by one or two substituents independently selected from:

loweralkyl, lower-alkoxy, cycloalkoxy, haloalkyl, cycloalkylalkoxy, alkoxyalkyl, alkoxyalkoxy, benzyloxyalkoxy, hydroxyalkyl, hydroxycycloalkyl, hydroxyfluoroalkyl, aminoalkyl, alkyl-sulfonyl, hydroxyalkoxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, cycloalkylamino, N-alkyl-N-cycloalkylamino, halo, deuteroalkoxy-alkyl, haloalkoxy, cycloamino, cyclic ether-substituted amino, hydroxy-cycloamino, loweralkoxy-cycloamino, hydroxyalkylamino, amino-haloloweralkyl, deuteroloweralkylamino, cyanoalkyl, cyanocycloalkyl, carbamoyl, piperazinyl, alkylsulfonamido, dialkylsulfonamido, alkylsulfonamidoalkyl, dialkylsulfonamido(alkyl), 3H-tetrazol-5-yl, alkylcarbonylaminoalkyl, alkylcarbonyl-N-alkylamino, nitro, alkylaminocarbonylalkyl, alkoxyalkylaminocarbonyl, morpholinyl, 1H-pyrazolyl, loweralkylsubstituted(1H-imidazol-1-yl).

In an embodiment, specifically preferred unsubstituted or substituted heterocyclyl or heteroaryl for R³ is selected from:

-   -   pyridyl, e.g. pyrid-2-yl, pyrid-3-yl or pyrid-4-yl; especially         pyrid-3-yl;     -   alkylpyridyl, in particular loweralkylpyridyl, e.g.         methylpyridyl, e.g., 2-, 3- or 4-methylpyridyl, especially         2-methylpyridyl or 3-methylpyridyl, in particular         2-methylpyrid-5-yl or 3-methylpyrid-5-yl;     -   alkoxypyridyl, in particular lower-alkoxypyridyl, e.g.         methoxypyridyl, e.g., 2-, 3- or 4-methoxypyridyl, especially         2-methoxypyridyl or 3-methoxypyridyl (in particular         2-methoxypyridin-5-yl, 3-methoxypyridin-5-yl); ethoxypyridyl,         e.g., 2-, 3- or 4-ethoxypyridyl especially 2-ethoxypyridyl or         3-ethoxypyridyl (in particular 3-ethoxypyrid-5-yl,         2-ethoxypyrid-5-yl, 2-ethoxypyrid-4-yl); propoxypyridyl, e.g.         n-propoxypyridyl or iso-propoxypyridyl (in particular         6-(n-propoxy)pyrid-3-yl or 3-(iso-propoxy)pyridin-5-yl or         2-(iso-propoxy)pyridin-4-yl);     -   cycloalkoxypyridyl, e.g. cyclobutoxy-pyridyl, especially         3-cyclobutoxy-pyridyl (in particular 3-cyclobutoxy-pyrid-5-yl);     -   (haloalkoxy)pyridyl e.g. (halo-isopropoxy)pyridyl, such as         3-(1,3-difluoropropan-2-yloxy)-pyridyl (in particular         3-(1,3-difluoropropan-2-yloxy)-pyrid-5-yl) or         3-(2-fluoroethan-1-yloxy)-pyridyl (in particular         3-(2-fluoroethan-1-yloxy)-pyrid-5-yl) or         3-(difluoromethyloxy)-pyridyl (in particular         3-(difluoromethyloxy)-pyrid-5-yl);     -   cycloalkylalkoxypyridyl, e.g. cyclopropylmethoxy-pyridyl,         especially 2-cyclopropylmethoxy-pyridyl (in particular         2-cyclopropylmethoxy-pyrid-5-yl);     -   alkoxyalkylpyridyl e.g. ethoxymethylpyridyl,         2-methoxymethylpyridyl (in particular 2-methoxymethylpyrid-5-yl)         or 3-methoxymethylpyridyl (in particular         3-methoxymethylpyrid-5-yl) or 3-(2-methoxy-prop-2-yl)pyridyl (in         particular 3-(2-methoxy-prop-2-yl)pyrid-5-yl or         3-(2-ethoxy-prop-2-yl)pyridyl (in particular         3-(2-ethoxy-prop-2-yl)pyrid-5-yl;     -   alkoxyalkoxypyridyl, in particular methoxyethoxypyridyl, e.g.         3-(2-methoxyethoxy)pyridyl or 2-(2-methoxyethoxy)pyridyl (in         particular 3-(2-methoxyethoxy)pyrid-5-yl or         2-(2-methoxyethoxy)pyrid-5-yl);     -   (alkyl)(alkoxyalkoxy)pyridyl, in particular         (loweralkyl)(loweralkoxyalkoxy)pyridyl, such as         (methyl)(methoxyethoxy)pyridyl, e.g.         (2-methyl)-(3-(2-methoxyethoxy)) pyridyl (in particular         (2-methyl)-(3-(2-methoxyethoxy)) pyrid-5-yl;     -   benzyloxyalkoxypyridyl, in particular benzyloxyethoxypyridyl or         benzyloxypropoxypyridyl, e.g. 2-benzyloxyethoxypyridyl or         3-benzyloxypropoxypyridyl (in particular         2-benzyloxyethoxypyrid-5-yl or 3-benzyloxypropoxy pyrid-5-yl);     -   hydroxyalkylpyridyl, e.g. hydroxymethylpyridyl, especially         2-(hydroxymethyl)-pyridyl (in particular         2-hydroxymethylpyrid-5-yl) or hydroxyethylpyridyl, especially         3-(1-hydroxyethyl)-pyridyl (in particular         3-(1-hydroxyethyl)pyrid-5-yl) or hydroxypentylpyridyl         (alternatively termed 1-hydroxy-1-ethyl-propyl), such as         3-(3-hydroxypentyl)-pyridyl especially         3-(3-hydroxypent-3-yl)pyridyl (in particular         3-(3-hydroxypent-3-yl)pyrid-5-yl) or hydroxypropylpyridyl,         especially 3-(2-hydroxyprop-2-yl)-pyridyl (in particular         3-(2-hydroxyprop-2-yl)pyrid-5-yl) or         hydroxy-1,1-dimethyl-ethylpyridyl, especially         3-(2-hydroxy-1,1-dimethyl-ethyl)-pyridyl (in particular         3-(2-hydroxy-1,1-dimethyl-ethyl)pyrid-5-yl);     -   hydroxycycloalkylpyridyl, e.g. hydroxylowercycloalkylpyridyl,         especially 3-(1-hydroxycyclopentyl)-pyridyl (in particular         3-(1-hydroxycyclopentyl)-pyrid-5-yl);     -   hydroxyfluoroalkylpyridyl, e.g. hydroxyfluoropropylpyridyl,         especially 3-(1,3-difluoro-2-hydroxyprop-2-yl)-pyridyl (in         particular 3-(1,3-difluoro-2-hydroxyprop-2-yl)pyrid-5-yl)     -   aminoalkylpyridyl, e.g. aminomethylpyridyl, especially         3-(aminomethyl)-pyridyl (in particular 3-aminomethylpyrid-5-yl);     -   alkyl-sulfonyl pyridyl, e.g. methanesulfonylpyridyl, especially         3-methanesulfonylpyridyl (in particular         3-methanesulfonylpyrid-5-yl);     -   hydroxyalkoxypyridyl, e.g. 2-(2-hydroxyethoxy)-pyridyl or         2-(3-hydroxypropoxy)-pyridyl (in particular         2-(2-hydroxyethoxy)-pyrid-5-yl or         2-(3-hydroxypropoxy)-pyrid-5-yl);     -   alkoxycarbonylpyridyl, e.g. methoxycarbonylpyridyl, especially         2-methoxycarbonyl-pyridyl (in particular         2-methoxycarbonyl-pyrid-5-yl);     -   aminopyridyl, e.g. 2- or 3-aminopyridyl (in particular         2-aminopyrid-5-yl or 3-aminopyrid-5-yl);     -   alkylaminopyridyl, e.g. loweralkylaminopyridyl, in particular         methylaminopyridyl such as 2-methylaminopyridyl,         3-methylaminopyridyl or ethylaminopyridyl such as         2-ethylaminopyridyl (especially 2-methylaminopyrid-5-yl,         3-methylaminopyrid-5-yl or 3-ethylaminopyrid-5-yl) or         isopropylaminopyridyl such as 3-isopropylaminopyridyl         (especially 3-isopropylaminopyrid-5-yl;     -   dialkylaminopyridyl, in particular di-loweralkylaminopyridyl,         e.g. 2-, 3- or 4-dimethylaminopyridyl, especially         2-dimethylaminopyridyl or 3-dimethylaminopyridyl (in particular         2-dimethylaminopyrid-5-yl or 3-dimethylaminopyrid-5-yl) or e.g.         2-, 3- or 4-diethylaminopyridyl, especially         2-diethylaminopyridyl or 3-diethylaminopyridyl (in particular         2-diethylaminopyrid-5-yl or 3-diethylaminopyrid-5-yl) or e.g.         2-, 3- or 4-ethylmethylaminopyridyl especially         2-ethylmethylaminopyridyl (in particular         2-ethylmethylaminopyrid-5-yl or 3-ethylmethylaminopyridyl (in         particular 3-ethylmethylaminopyrid-5-yl) or e.g. 2-, 3- or         4-isopropylmethylaminopyridyl, especially         2-isopropylmethylaminopyridyl or 3-isopropyl methylaminopyridyl         (in particular 2-isopropylmethylaminopyrid-5-yl or 3-isopropyl         methylaminopyrid-5-yl;     -   cycloalkylaminopyridyl, e.g. cycloloweralkylaminopyridyl, in         particular cyclobutylaminopyridyl such as         3-cyclobutylaminopyridyl or (especially         3-methylaminopyrid-5-yl);     -   (N-alkyl-N-cycloalkylamino)pyridyl, e.g.         (N-loweralkyl-N-cycloloweralkylamino)pyridyl, in particular         (N-methyl-N-cyclobutylamino)pyridyl such as         3-(N-methyl-N-cyclobutylamino)pyridyl or (especially         3-(N-methyl-N-cyclobutylamino)pyrid-5-yl);     -   (alkyl)(amino)pyridyl, e.g. (loweralkyl)(amino)pyridyl, in         particular (methyl)(amino)pyridyl such as         2-methyl-3-amino-pyridyl (especially         2-methyl-3-amino-pyrid-5-yl) or (ethyl)(amino)pyridyl such as         2-ethyl-3-amino-pyridyl (especially 2-ethyl-3-amino-pyrid-5-yl);     -   (halo)(amino)pyridyl, e.g. (fluoro)(amino)pyridyl, in particular         3-fluoro-2-amino-pyridyl (especially         3-fluoro-2-amino-pyrid-5-yl), 2-fluoro-3-amino-pyridyl         (especially 2-fluoro-3-amino-pyrid-5-yl),         3-chloro-2-amino-pyridyl (especially         3-chloro-2-amino-pyrid-5-yl) or 2-chloro-3-amino-pyridyl         (especially 2-chloro-3-amino-pyrid-5-yl);     -   (halo)(alkylamino)pyridyl, e.g. (halo)(loweralkylamino)pyridyl,         in particular (fluoro)(methylamino)pyridyl such as         3-fluoro-2-methylamino-pyridyl (especially         3-fluoro-2-methylamino-pyrid-5-yl),         2-fluoro-3-methylamino-pyridyl (especially         2-fluoro-3-methylamino-pyrid-5-yl),         2-fluoro-3-ethylamino-pyridyl (especially         2-fluoro-3-ethylamino-pyrid-5-yl),         3-chloro-2-methylamino-pyridyl (especially         3-chloro-2-methylamino-pyrid-5-yl),         3-chloro-2-ethylamino-pyridyl (especially         3-chloro-2-ethylamino-pyrid-5-yl) or         2-chloro-3-ethylamino-pyridyl (especially         2-chloro-3-ethylamino-pyrid-5-yl);     -   (halo)(dialkylamino)pyridyl, e.g.         (halo)(di-loweralkylamino)pyridyl, in particular         (fluoro)(dimethylamino)pyridyl such as         2-fluoro-3-dimethylamino-pyridyl (especially         2-fluoro-3-dimethylamino-pyrid-5-yl);     -   (halo)(hydroxyalkyl)pyridyl, e.g.         (halo)(hydroxyloweralkyl)pyridyl, in particular         (chloro)(hydroxymethyl)pyridyl such as         3-chloro-2-hydroxymethyl-pyridyl (especially         3-chloro-2-hydroxymethyl-pyrid-5-yl)     -   (alkoxy)(alkyl)pyridyl e.g. (methoxy)(methyl)pyridyl, such as         3-methoxy-2-methyl-pyridyl (in particular         3-methoxy-2-methyl-pyrid-5-yl), (ethoxy)(methyl)pyridyl, such as         3-ethoxy-2-methyl-pyridyl (in particular         3-ethoxy-2-methyl-pyrid-5-yl) or e.g. (propoxy)(methyl)pyridyl,         such as 3-propoxy-2-methyl-pyridyl (in particular         3-propoxy-2-methyl-pyrid-5-yl) or e.g. (propoxy)(ethyl)pyridyl,         such as 3-propoxy-2-ethyl-pyridyl (in particular         3-propoxy-2-ethyl-pyrid-5-yl) or e.g. (ethoxy)(ethyl)pyridyl,         such as 3-ethoxy-2-ethyl-pyridyl (in particular         3-ethoxy-2-ethyl-pyrid-5-yl);     -   (alkoxy)(alkoxy)pyridyl e.g. (propoxy)(methoxy)pyridyl, such as         3-propoxy-2-methoxy-pyridyl (in particular         3-propoxy-2-methoxy-pyrid-5-yl); or e.g.         (propoxy)(ethoxy)pyridyl, such as 3-propoxy-2-ethoxy-pyridyl (in         particular 3-propoxy-2-ethoxy-pyrid-5-yl) or e.g.         (methoxy)(methoxy)pyridyl, such as 3-methoxy-2-methoxy-pyridyl         (in particular 3-methoxy-2-methoxy-pyrid-5-yl) or e.g.         (ethoxy)(methoxy)pyridyl, such as 3-ethoxy-2-methoxy-pyridyl (in         particular 3-ethoxy-2-methoxy-pyrid-5-yl);     -   (alkoxy)(alkoxyalkyl)pyridyl e.g.         (isopropoxy)(methoxymethyl)pyridyl, such as         3-isopropoxy-2-methoxymethyl-pyridyl (in particular         3-isopropoxy-2-methoxymethyl-pyrid-5-yl) or         (methoxy)(methoxymethyl)pyridyl, such as         3-methoxy-2-methoxymethyl-pyridyl or         2-methoxy-3-methoxymethyl-pyridyl (in particular         3-methoxy-2-methoxymethyl-pyrid-5-yl or         2-methoxy-3-methoxymethyl-pyrid-5-yl) or         (methoxy)(ethoxymethyl)pyridyl, such as         3-methoxy-2-ethoxymethyl-pyridyl (in particular         3-methoxy-2-ethoxymethyl-pyrid-5-yl) or         (ethoxy)(methoxymethyl)pyridyl, such as         3-ethoxy-2-methoxymethyl-pyridyl (in particular         3-ethoxy-2-methoxymethyl-pyrid-5-yl);     -   (alkoxy)(deuteroalkoxy-alkyl)pyridyl e.g.         (ethoxy)(trideuteromethoxymethyl)pyridyl, such as         3-ethoxy-2-trideuteromethoxymethyl-pyridyl (in particular         3-ethoxy-2-trideuteromethoxymethyl-pyrid-5-yl);     -   (alkoxy)(hydroxyalkyl)pyridyl e.g.         (isopropoxy)(hydroxymethyl)pyridyl, such as         3-isopropoxy-2-hydroxymethyl-pyridyl (in particular         3-isopropoxy-2-hydroxymethyl-pyrid-5-yl) or         (methoxy)(hydroxymethyl)pyridyl, such as         3-methoxy-2-hydroxymethyl-pyridyl (in particular         3-methoxy-2-hydroxymethyl-pyrid-5-yl) or         2-methoxy-3-hydroxymethyl-pyridyl (in particular         2-methoxy-3-hydroxymethyl-pyrid-5-yl) or         (ethoxy)(hydroxymethyl)pyridyl, such as         3-ethoxy-2-hydroxymethyl-pyridyl (in particular         3-ethoxy-2-hydroxymethyl-pyrid-5-yl);     -   (haloalkoxy)(alkyl)pyridyl e.g.         (halo-isopropoxy)(methyl)pyridyl, such as         3-(1,3-difluoropropan-2-yloxy)-2-(methyl)-pyridyl (in particular         3-(1,3-difluoropropan-2-yloxy)-2-(methyl)-pyrid-5-yl);     -   (haloalkoxy)(hydroxyalkyl)pyridyl e.g.         (halo-isopropoxy)(hydroxymethyl)pyridyl, such as         3-(1,3-difluoropropan-2-yloxy)-2-(hydroxymethyl)-pyridyl (in         particular         3-(1,3-difluoropropan-2-yloxy)-2-(hydroxymethyl)-pyrid-5-yl);     -   (alkoxyalkoxy)(hydroxyalkyl)pyridyl, in particular (loweralkoxy         loweralkoxy)(hydroxyloweralkyl)pyridyl, e.g.         (methoxyethoxy)(hydroxymethyl)pyridyl, such as         3-methoxyethoxy-2-hydroxymethyl-pyridyl (in particular         3-methoxyethoxy-2-hydroxymethyl-pyrid-5-yl);     -   (alkyl)(alkylamino)pyridyl, e.g.         (loweralkyl)(loweralkylamino)pyridyl, in particular         (methyl)(ethylamino)pyridyl such as         2-methyl-3-ethylamino-pyridyl (especially         2-methyl-3-ethylamino-pyrid-5-yl) or         (methyl)(methylamino)pyridyl such as         3-methyl-2-methylamino-pyridyl (especially         3-methyl-2-methylamino-pyrid-5-yl) or (ethyl)(ethylamino)pyridyl         such as 2-ethyl-3-ethylamino-pyridyl (especially         2-methyl-3-ethylamino-pyrid-5-yl) or         (ethyl)(isopropylamino)pyridyl such as         2-ethyl-3-isopropylamino-pyridyl (especially         2-ethyl-3-isopropylamino-pyrid-5-yl);     -   (alkyl)(di-alkylamino)pyridyl, e.g.         (loweralkyl)(di-loweralkylamino)pyridyl, in particular         (methyl)(N-methyl-N-ethylamino)pyridyl such as         2-methyl-3-(N-methyl-N-ethylamino)-pyridyl (especially         2-methyl-3-(N-methyl-N-ethylamino)-pyrid-5-yl) or         (methyl)(N,N-dimethylamino)pyridyl such as         2-methyl-3-(N,N-dimethylamino)-pyridyl (especially         2-methyl-3-(N,N-dimethylamino)-pyrid-5-yl);     -   cycloaminopyridyl, e.g. azetidinylpyridyl, especially         2-azetidin-1-yl-pyridinyl (in particular         2-azetidin-1-yl-pyridin-5-yl) or 3-azetidin-1-yl-pyridinyl (in         particular 3-azetidin-1-yl-pyridin-5-yl) or pyrrolidinylpyridyl,         especially 2-pyrrolidinyl-1-yl-pyridinyl (in particular         2-pyrrolidinyl-1-yl-pyridin-5-yl);     -   cyclic ether-substituted amino-pyridyl, e.g.         tetrahydro-pyranylamino-pyridyl, especially         2-(tetrahydro-pyran-4-ylamino)-pyridyl (in particular         2-(tetrahydro-pyran-4-ylamino)pyridyl-5-yl;     -   hydroxy-cycloaminopyridyl, such as hydroxy-pyrrolidinylpyridyl,         e.g. 3-hydroxy-pyrrolidin-1-yl-pyridinyl (in particular         6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl, more particularly,         6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl or         6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl;     -   loweralkoxy-cycloaminopyridyl, such as         methoxy-pyrrolidinylpyridyl, e.g.         3-methoxy-pyrrolidin-1-yl-pyridinyl (in particular         6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl, more particularly,         6-((R)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl or         6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl;     -   hydroxyalkylaminopyridyl, e.g. 2-(2-hydroxyethylamino)-pyridyl         (in particular 2-(2-hydroxyethylamino)-pyrid-5-yl);     -   (alkyl)(hydroxy)pyridyl, in particular         (loweralkyl)(hydroxy)pyridyl e.g. 2-(methyl)-3-(hydroxy)-pyridyl         (in particular 2-(methyl)-3-(hydroxy)-pyrid-5-yl) or         2-(ethyl)-3-(hydroxy)-pyridyl (in particular         2-(ethyl)-3-(hydroxy)-pyrid-5-yl);     -   (hydroxyalkyl)(alkylamino)pyridyl, in particular         (hydroxyloweralkyl)(loweralkylamino)pyridyl, such as         (hydroxymethyl)(ethylamino)-pyridyl, e.g.         2-(hydroxymethyl)-3-(ethylamino)-pyridyl (in particular         2-(hydroxymethyl)-3-(ethylamino)-pyrid-5-yl) or such as         (hydroxymethyl)(methylamino)-pyridyl, e.g.         2-(hydroxymethyl)-3-(methylamino)-pyridyl (in particular         2-(hydroxymethyl)-3-(methylamino)-pyrid-5-yl)3-(hydroxymethyl)-2-(methylamino)-pyridyl         (in particular 3-(hydroxymethyl)-2-(methylamino)-pyrid-5-yl);     -   (hydroxyalkyl)(amino)pyridyl, in particular         (hydroxyloweralkyl)(amino)pyridyl, such as         (hydroxymethyl)(amino)-pyridyl, e.g.         3-(hydroxymethyl)-2-(amino)-pyridyl (in particular         3-(hydroxymethyl)-2-(amino)-pyrid-5-yl);     -   (alkoxyalkyl)(alkylamino)pyridyl, in particular         (loweralkoxyloweralkyl)(loweralkylamino)pyridyl, such as         (methoxymethyl)(ethylamino)-pyridyl, e.g.         2-(methoxymethyl)-3-(ethylamino)-pyridyl (in particular         2-(methoxymethyl)-3-(ethylamino)-pyrid-5-yl) or such as         (methoxymethyl)(methylamino)-pyridyl, e.g.         2-(methoxymethyl)-3-(methylamino)-pyridyl (in particular         2-(methoxymethyl)-3-(methylamino)-pyrid-5-yl or or such as         (ethoxymethyl)(ethylamino)-pyridyl, e.g.         3-(ethoxymethyl)-2-(ethylamino)-pyridyl (in particular         3-(ethoxymethyl)-2-(methylamino)-pyrid-5-yl;     -   (alkoxyalkyl)(amino)pyridyl, in particular         (alkoxyloweralkyl)(amino)pyridyl, such as         (ethoxymethyl)(amino)-pyridyl, e.g.         3-(ethoxymethyl)-2-(amino)-pyridyl (in particular         3-(ethoxymethyl)-2-(amino)-pyrid-5-yl) or         (methoxymethyl)(amino)-pyridyl, e.g.         3-(methoxymethyl)-2-(amino)-pyridyl (in particular         3-(methoxymethyl)-2-(amino)-pyrid-5-yl);     -   amino-haloloweralkyl-pyridyl, e.g.         amino-trifluoromethyl-pyridyl, especially         2-amino-3-trifluoromethyl-pyridyl (in particular         2-amino-3-trifluoromethyl-pyrid-5-yl);     -   alkylamino-haloalkyl-pyridyl, such as         loweralkylamino-haloloweralkyl-pyridyl, e.g.         methylamino-trifluoromethyl-pyridyl, especially         2-methylamino-3-trifluoromethyl-pyridyl (in particular         2-methylamino-3-trifluoromethyl-pyrid-5-yl) or e.g.         ethylamino-trifluoromethyl-pyridyl, especially         2-ethylamino-3-trifluoromethyl-pyridyl (in particular         2-ethylamino-3-trifluoromethyl-pyrid-5-yl);     -   haloalkyl-deuteroloweralkylamino-pyridyl, e.g.         trifluoromethyl-trideuteromethylamino-pyridyl, especially         3-trifluoromethyl-2-trideuteromethylamino-pyridyl (in particular         3-trifluoromethyl-2-trideuteromethylamino-pyrid-5-yl);     -   haloalkylpyridinyl, in particular haloloweralkylpyridyl,         especially, 2-, 3- or 4-trifluoromethylpyridyl, most especially         2-trifluoromethylpyridyl (in particular         2-trifluoromethylpyrid-5-yl);     -   cyanoalkylpyridinyl, in particular cyanoloweralkylpyridyl,         especially, cyanopropylpyridyl, most especially         2-cyanoprop-2-ylpyridyl (in particular         3-(2-cyanoprop-2-yl)-pyrid-5-yl);     -   cyanocycloalkylpyridinyl, in particular         cyanolowercycloalkylpyridyl, especially, cyanocyclobutylpyridyl,         most especially 1-cyanocyclobutylpyridyl (in particular         3-(1-cyanocyclobutyl)-pyrid-5-yl);     -   halopyridyl, in particular fluoropyridyl, especially         2-fluoropyridyl (in particular 2-fluoropyrid-3-yl or         2-fluoropyrid-4-yl);     -   halo-alkoxy-pyridyl, e.g. fluoro-methoxy-pyridyl such as         3-fluoro-2-methoxy-pyridyl (in particular         3-fluoro-2-methoxy-pyrid-5-yl);     -   carbamoylpyridyl, especially 2-(carbamoyl)pyridyl (in particular         2-(carbamoyl)pyrid-5-yl); alkyl-substituted carbamoyl, e.g.         methylcarbamoyl, especially 2-(methylcarbamoyl)pyridyl (in         particular 2-(methylcarbamoyl)pyrid-5-yl);     -   piperazinylpyridyl, e.g. 1-piperazinylpyridyl, especially         2-(1-piperazinyl)pyridyl (in particular         2-(1-piperazinyl)pyrid-5-yl); N-alkylpiperazinylpyridyl, such as         N-loweralkylpiperazinylpyridyl, e.g. N-methylpiperazinylpyridyl,         especially 2-(4-methylpiperazin-1-yl)-pyridyl (in particular         2-(4-methylpiperazin-1-yl)-pyrid-5-yl);     -   alkylsulfonamidopyridyl, such as loweralkylsulfonamidopyridyl,         especially methylsulfonamidopyridyl, e.g. 3-(methylsulfonamido)         pyridyl (in particular 3-(methylsulfonamido)-pyridin-5-yl);     -   dialkylsulfonamidopyridyl, such as         diloweralkylsulfonamidopyridyl, especially         dimethylsulfonamidopyridyl, e.g. 3-(dimethylsulfonamido) pyridyl         (in particular 3-(dimethylsulfonamido)-pyridin-5-yl);     -   (alkylsulfonamido)(alkyl)pyridyl such as         (loweralkylsulfonamido)(loweralkyl)pyridyl, especially         (methylsulfonamido)(methyl)pyridyl, e.g.         3-(methylsulfonamido)(methyl)pyridyl (in particular         3-(methylsulfonamido)-2-methylpyridin-5-yl);     -   (alkylsulfonamido)(halo)pyridyl such as         (loweralkylsulfonamido)(chloro)pyridyl, especially         (methylsulfonamido)(chloro)pyridyl, e.g.         3-(methylsulfonamido)(chloro)pyridyl (in particular         3-(methylsulfonamido)-2-chloro-pyridin-5-yl);     -   (alkylsulfonamidoalkyl)pyridyl such as         (loweralkylsulfonamido-loweralkyl)pyridyl, especially         (methylsulfonamidomethyl)pyridyl, e.g.         3-(methylsulfonamidomethyl)pyridyl (in particular         3-(methylsulfonamidomethyl)-pyridin-5-yl);     -   dialkylsulfonamido(alkyl)pyridyl, such as         diloweralkylsulfonamido(loweralkyl)pyridyl, especially         dimethylsulfonamido(methyl)pyridyl, e.g.         3-(dimethylsulfonamido)(2-methyl)pyridyl (in particular         3-(dimethylsulfonamido)-(2-methyl)-pyridin-5-yl);     -   3H-tetrazol-5-yl pyridyl, e.g. 2-(3H-tetrazol-5-yl)pyridyl (in         particular 2-(3H-tetrazol-5-yl)pyrid-5-yl);     -   alkylcarbonylaminoalkylpyridyl, such as         loweralkylcarbonylaminoloweralkyl)pyridyl, e.g.         methylcarbonylaminomethylpyridyl, especially         3-methylcarbonylaminomethylpyridyl (in particular         3-methylcarbonylaminomethylpyrid-5-yl);     -   (halo)(alkylcarbonylamino)pyridyl, such as         (halo)(loweralkylcarbonylamino)pyridyl, e.g.         (chloro)(methylcarbonylamino)pyridyl, especially         2-(chloro)-3-(methylcarbonylamino)pyridyl (in particular         2-(chloro)-3-(methylcarbonylamino)pyrid-5-yl);     -   (alkoxy)(alkylcarbonylamino)pyridyl, such as         (loweralkoxy)(loweralkylcarbonylamino)pyridyl, e.g.         (methoxy)(methylcarbonylamino)pyridyl or         (ethoxy)(methylcarbonylamino)pyridyl, especially         2-(methoxy)-3-(methylcarbonylamino)pyridyl or         2-(ethoxy)-3-(methylcarbonylamino)pyridyl (in particular         2-(methoxy)-3-(methylcarbonylamino)pyrid-5-yl or         2-(ethoxy)-3-(methylcarbonylamino)pyrid-5-yl);     -   (alkoxy)(alkylcarbonyl-N-alkylamino)pyridyl, such as         (loweralkoxy)(loweralkylcarbonyl-N-loweralkylamino)pyridyl, e.g.         (methoxy)(methylcarbonyl-N-methylamino)pyridyl or         (ethoxy)(methylcarbonyl-N-methylamino)pyridyl, especially         2-(methoxy)-3-(methylcarbonyl-N-methylamino)pyridyl or         2-(ethoxy)-3-(methylcarbonyl-N-methylamino)pyridyl (in         particular         2-(methoxy)-3-(methylcarbonyl-N-methylamino)pyrid-5-yl or         2-(ethoxy)-3-(methylcarbonyl-N-methylamino)pyrid-5-yl);     -   (alkoxy)(nitro)pyridyl, such as (loweralkoxy)(nitro)pyridyl,         e.g. (methoxy)(nitro)pyridyl, especially         2-(methoxy)-3-(nitro)-pyridyl (in particular         2-(methoxy)-3-(nitro)-pyrid-5-yl);     -   (alkoxy)(cyano) pyridyl, such as (loweralkoxy)(cyano) pyridyl,         e.g. (methoxy)(cyano)pyridyl, especially         2-(methoxy)-3-(cyano)-pyridyl (in particular         2-(methoxy)-3-(cyano)-pyrid-5-yl);     -   (alkoxy)(amino)pyridyl, such as (loweralkoxy)(amino)pyridyl,         e.g. (methoxy)(amino)pyridyl, especially         2-(methoxy)-3-(amino)-pyridyl (in particular         2-(methoxy)-3-(amino)-pyrid-5-yl);     -   (alkoxy)(alkylamino)pyridyl, such as         (loweralkoxy)(alkylamino)pyridyl, e.g.         (methoxy)(ethylamino)pyridyl, especially         2-(methoxy)-3-(ethylamino)pyridyl (in particular         2-(methoxy)-3-(ethylamino)pyrid-5-yl;     -   (alkoxyalkyl)(alkylamino)pyridyl, such as         (loweralkoxyloweralkyl)(alkylamino)pyridyl, e.g.         (methoxymethyl)(methylamino)pyridyl, especially         3-(methoxymethyl)-2-(methylamino)pyridyl (in particular         3-(methoxymethyl)-2-(methylamino)pyrid-5-yl) or         (methoxymethyl)(ethylamino)pyridyl, especially         3-(methoxymethyl)-2-(ethylamino)pyridyl (in particular         3-(methoxymethyl)-2-(ethylamino)pyrid-5-yl);     -   (alkoxy)(alkylaminocarbonyl)pyridyl, such as         (loweralkoxy)(loweralkylaminocarbonyl)pyridyl, e.g.         (methoxy)(methylaminocarbonyl)pyridyl, especially         2-(methoxy)-3-(methylaminocarbonyl)pyridyl (in particular         2-(methoxy)-3-(methylaminocarbonyl)pyrid-5-yl;     -   alkylaminocarbonylalkylpyridyl, such as         loweralkylaminocarbonylloweralkylpyridyl, e.g.         methylaminocarbonylmethylpyridyl, especially         3-methylaminocarbonylmethylpyridyl (in particular         3-methylaminocarbonylmethylpyrid-5-yl;     -   (amino)(alkylaminocarbonyl)pyridyl, such as         (amino)(loweralkylaminocarbonyl)pyridyl, e.g.         (amino)(methylaminocarbonyl)pyridyl, especially         2-(amino)-3-(methylaminocarbonyl)pyridyl (in particular         2-(amino)-3-(methylaminocarbonyl)pyrid-5-yl) or         (amino)(ethylaminocarbonyl)pyridyl, especially         2-(amino)-3-(ethylaminocarbonyl)pyridyl (in particular         2-(amino)-3-(ethylaminocarbonyl)pyrid-5-yl) or         (amino)(isopropylaminocarbonyl)pyridyl, especially         2-(amino)-3-(isopropylaminocarbonyl)pyridyl (in particular         2-(amino)-3-(isopropylaminocarbonyl)pyrid-5-yl);     -   (amino)(alkoxyalkylaminocarbonyl)pyridyl, such as         amino)(loweralkoxyloweralkylaminocarbonyl)pyridyl, e.g.         (amino)(methoxyethylaminocarbonyl)pyridyl, especially         2-(amino)-3-(2-methoxyethylaminocarbonyl)pyridyl (in particular         2-(amino)-3-(2-methoxyethylaminocarbonyl)pyrid-5-yl)     -   (alkylamino)(alkylaminocarbonyl)pyridyl, such as         (loweralkylamino)(loweralkylaminocarbonyl)pyridyl, e.g.         (methylamino)(ethylaminocarbonyl)pyridyl, especially         2-(methylamino)-3-(ethylaminocarbonyl)pyridyl (in particular         2-(methylamino)-3-(ethylaminocarbonyl)pyrid-5-yl);     -   (alkoxy)(aminocarbonyl)pyridyl, such as         (loweralkoxy)(aminocarbonyl)pyridyl, e.g.         (methoxy)(aminocarbonyl)pyridyl, especially         2-(methoxy)-3-(aminocarbonyl)pyridyl (in particular         2-(methoxy)-3-(aminocarbonyl)pyrid-5-yl);     -   (alkoxy)(hydroxycarbonyl)pyridyl, such as         (loweralkoxy)(hydroxycarbonyl)pyridyl, e.g.         (methoxy)(hydroxycarbonyl)pyridyl, especially         2-(methoxy)-3-(hydroxycarbonyl)pyridyl (in particular         2-(methoxy)-3-(hydroxycarbonyl)pyrid-5-yl;     -   morpholinylpyridinyl, such as morpholin-4-ylpyridinyl, e.g.         3-morpholin-4-ylpyridinyl, especially         3-morpholin-4-ylpyridin-5-yl;     -   (1H-pyrazolyl)-pyridinyl, such as (1H-pyrazol-1yl)-pyridinyl,         especially 2-(1H-pyrazol-1yl)-pyridinyl, in particular         (1H-pyrazol-1yl)-pyridin-5-yl;     -   loweralkylsubstituted(1H-imidazol-1-yl)-pyridinyl, such as         methyl-substituted(1H-imidazol-1-yl)-pyridinyl, e.g.         (2-methyl-1H-imidazol-1-yl)-pyridinyl, especially         (2-methyl-1H-imidazol-1-yl)-pyridin-5-yl;     -   pyrimidinyl, in particular pyrimidin-5-yl;     -   di-loweralkylaminopyrimidinyl, e.g. 2- or         4-dimethylaminopyrimidinyl, especially         2-dimethylaminopyrimidinyl (in particular         2-dimethylaminopyrimidin-5-yl);     -   alkoxypyrimidinyl, in particular methoxypyrimidinyl or         ethoxypyrimidinyl, e.g. 2-methoxypyrimidinyl or         2-ethoxypyrimidinyl (in particular 2-methoxypyrimidin-5-yl or         2-ethoxypyrimidin-5-yl);     -   di-alkoxypyrimidinyl, in particular di-methoxypyrimidinyl, e.g.         2,4-dimethoxypyrimidinyl or (in particular         2,4-dimethoxypyrimidin-5-yl);     -   (alkylamino)(alkoxy)pyrimidinyl, in particular         (loweralkylamino)(loweralkoxy)pyrimidinyl, e.g.         (methylamino)(methoxy)pyrimidinyl or         (ethylamino)(methoxy)pyrimidinyl e.g.         2-(methylamino)-4-(methoxy)pyrimidinyl or         2-(ethylamino)-4-(methoxy)pyrimidinyl (in particular         2-(methylamino)-4-(methoxy)pyrimidin-5-yl or         2-(ethylamino)-4-(methoxy)pyrimidin-5-yl);     -   cycloaminopyrimidinyl, e.g. pyrrolidinylpyrimidinyl, especially         2-(pyrrolidinyl)pyrimidinyl (in particular         2-(pyrrolidinyl)pyrimidin-5-yl);     -   aminopyrimidinyl, in particular 2-aminopyrimidinyl (especially         2-aminopyrimidin-5-yl;     -   alkylaminopyrimidinyl, in particular loweralkylaminopyrimidinyl,         e.g. 2-methylaminopyrimidinyl (especially         2-methylaminopyrimidin-5-yl);     -   dialkylaminopyrimidinyl, in particular         di-loweralkylaminopyrimidinyl, e.g. 2-dimethylaminopyrimidinyl         (especially 2-dimethylaminopyrimidin-5-yl);     -   1H-pyrrolo[2,3-b]pyridinyl (in particular         1H-pyrrolo[2,3-b]pyridin-5-yl);     -   1-methyl-1H-pyrrolo[2,3-b]pyridinyl (in particular         1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl);     -   pyrazinyl;     -   pyrazolyl, e.g. pyrazol-4-yl;     -   substituted pyrazolyl, e.g. hydroxyalkylpyrazolyl, especially         1-(2-hydroxy-ethyl)-1H-pyrazolyl (in particular         1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl) or         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl (in         particular         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl);     -   quinolinyl (in particular quinolin-3-yl);     -   2-oxo-2,3-dihydro-1H-indol-5-yl;     -   1-methyl-2,3-dihydro-1H-indol-5-yl;     -   1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl (in particular         1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl,         1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl or         1-(2-methoxyethyl)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl;     -   3H-imidazo[4,5-b]pyridin-6-yl, e.g.         (3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;     -   3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, e.g.         (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl;     -   1H-pyrrolo[3,2-b]pyridinyl, e.g. 1H-pyrrolo[3,2-b]pyridin-6-yl;     -   1-methyl-1H-pyrrolo[3,2-b]pyridinyl, e.g.         1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl;     -   2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, e.g.         2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl, in         particular         1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl,         especially         1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl;     -   3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, e.g.         3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, in particular         4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, especially         4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl;     -   1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, in         particular         1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl;     -   2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl, e.g.         2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl, in         particular         1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl,         especially         1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl.

In another embodiment, specifically preferred unsubstituted or substituted heterocyclyl or heteroaryl for R³ is selected from:

-   -   pyridyl, e.g. pyrid-2-yl, pyrid-3-yl or pyrid-4-yl;     -   alkylpyridyl, in particular loweralkylpyridyl, e.g.         methylpyridyl, e.g., 2-, 3- or 4-methylpyridyl, especially         2-methylpyridyl or 3-methylpyridyl, in particular         2-methylpyrid-5-yl or 3-methylpyrid-5-yl;     -   alkoxypyridyl, in particular lower-alkoxypyridyl, e.g.         methoxypyridyl, e.g., 2-, 3- or 4-methoxypyridyl, especially         2-methoxypyridyl or 3-methoxypyridyl (in particular         2-methoxypyridin-5-yl, 3-methoxypyridin-5-yl); ethoxypyridyl,         e.g., 2-, 3- or 4-ethoxypyridyl especially 2-ethoxypyridyl or         3-ethoxypyridyl (in particular 3-ethoxypyrid-5-yl,         2-ethoxypyrid-5-yl, 2-ethoxypyrid-4-yl); propoxypyridyl, e.g.         n-propoxypyridyl or iso-propoxypyridyl (in particular         6-(n-propoxy)pyrid-3-yl or 3-(iso-propoxy)pyridin-5-yl);     -   cycloalkylalkoxypyridyl, e.g. cyclopropylmethoxy-pyridyl,         especially 2-cyclopropylmethoxy-pyridyl (in particular         2-cyclopropylmethoxy-pyrid-5-yl);     -   alkoxyalkylpyridyl e.g. ethoxymethylpyridyl,         2-methoxymethylpyridyl (in particular         2-methoxymethylpyrid-5-yl);     -   alkoxyalkoxypyridyl, in particular methoxyethoxypyridyl, e.g.         3-(2-methoxyethoxy)pyridyl or 2-(2-methoxyethoxy)pyridyl (in         particular 3-(2-methoxyethoxy)pyrid-5-yl or         2-(2-methoxyethoxy)pyrid-5-yl);     -   benzyloxyalkoxypyridyl, in particular benzyloxyethoxypyridyl or         benzyloxypropoxypyridyl, e.g. 2-benzyloxyethoxypyridyl or         3-benzyloxypropoxypyridyl (in particular         2-benzyloxyethoxypyrid-5-yl or 3-benzyloxypropoxy pyrid-5-yl);     -   hydroxyalkylpyridyl, e.g. hydroxymethylpyridyl, especially         2-(hydroxymethyl)-pyridyl (in particular         2-hydroxymethylpyrid-5-yl);     -   alkyl-sulfonyl pyridyl, e.g. methanesulfonylpyridyl, especially         3-methanesulfonylpyridyl (in particular         3-methanesulfonylpyrid-5-yl);     -   hydroxyalkoxypyridyl, e.g. 2-(2-hydroxyethoxy)-pyridyl or         2-(3-hydroxypropoxy)-pyridyl (in particular         2-(2-hydroxyethoxy)-pyrid-5-yl or         2-(3-hydroxypropoxy)-pyrid-5-yl);     -   alkoxycarbonylpyridyl, e.g. methoxycarbonylpyridyl, especially         2-methoxycarbonyl-pyridyl (in particular         2-methoxycarbonyl-pyrid-5-yl);     -   aminopyridyl, e.g. 2- or 3-aminopyridyl (in particular         2-aminopyrid-5-yl or 3-aminopyrid-5-yl);     -   alkylaminopyridyl, e.g. loweralkylaminopyridyl, in particular         methylaminopyridyl such as 2-methylaminopyridyl or         ethylaminopyridyl such as 2-ethylaminopyridyl (especially         2-methylaminopyrid-5-yl or 3-ethylaminopyrid-5-yl);     -   dialkylaminopyridyl, in particular di-loweralkylaminopyridyl,         e.g. 2-, 3- or 4-dimethylaminopyridyl, especially         2-dimethylaminopyridyl (in particular 2-dimethylaminopyrid-5-yl)         or e.g. 2-, 3- or 4-diethylaminopyridyl, especially         2-diethylaminopyridyl (in particular 3-diethylaminopyrid-5-yl)         or e.g. 2-, 3- or 4-ethylmethylaminopyridyl especially         2-ethylmethylaminopyridyl (in particular         2-ethylmethylaminopyrid-5-yl);     -   (alkyl)(amino)pyridyl, e.g. (loweralkyl)(amino)pyridyl, in         particular (methyl)(amino)pyridyl such as         2-methyl-3-amino-pyridyl (especially         2-methyl-3-amino-pyrid-5-yl);     -   (alkoxy)(amino)pyridyl, e.g. (loweralkoxy)(amino)pyridyl, in         particular (methoxy)(amino)pyridyl such as         2-methoxy-3-amino-pyridyl (especially         2-methoxy-3-amino-pyrid-5-yl);     -   (alkoxy)(alkyl)pyridyl e.g. (ethoxy)(methyl)pyridyl, such as         3-ethoxy-2-methyl-pyridyl (in particular         3-ethoxy-2-methyl-pyrid-5-yl) or e.g. (propoxy)(methyl)pyridyl,         such as 3-propoxy-2-methyl-pyridyl (in particular         3-propoxy-2-methyl-pyrid-5-yl);     -   (alkoxy)(alkoxy)pyridyl e.g. (propoxy)(methoxy)pyridyl, such as         3-propoxy-2-methoxy-pyridyl (in particular         3-propoxy-2-methoxy-pyrid-5-yl); or e.g.         (propoxy)(ethoxy)pyridyl, such as 3-propoxy-2-ethoxy-pyridyl (in         particular 3-propoxy-2-ethoxy-pyrid-5-yl);     -   (alkyl)(alkylamino)pyridyl, e.g.         (loweralkyl)(loweralkylamino)pyridyl, in particular         (methyl)(ethylamino)pyridyl such as         2-methyl-3-ethylamino-pyridyl (especially         2-methyl-3-ethylamino-pyrid-5-yl);     -   (alkyl)(di-alkylamino)pyridyl, e.g.         (loweralkyl)(di-loweralkylamino)pyridyl, in particular         (methyl)(N-methyl-N-ethylamino)pyridyl such as         2-methyl-3-(N-methyl-N-ethylamino)-pyridyl (especially         2-methyl-3-(N-methyl-N-ethylamino)-pyrid-5-yl)     -   cycloaminopyridyl, e.g. azetidinylpyridyl, especially         2-azetidin-1-yl-pyridinyl (in particular         2-azetidin-1-yl-pyridin-5-yl);     -   hydroxyalkylaminopyridyl, e.g. 2-(2-hydroxyethylamino)-pyridyl         (in particular 2-(2-hydroxyethylamino)-pyrid-5-yl);         amino-haloloweralkyl-pyridyl, e.g.         amino-trifluoromethyl-pyridyl, especially         2-amino-3-trifluoromethyl-pyridyl (in particular         2-amino-3-trifluoromethyl-pyrid-5-yl);     -   haloalkylpyridinyl, in particular haloloweralkylpyridyl,         especially, 2-, 3- or 4-trifluoromethylpyridyl, most especially         2-trifluoromethylpyridyl (in particular         2-trifluoromethylpyrid-5-yl);     -   halopyridyl, in particular fluoropyridyl, especially         2-fluoropyridyl (in particular 2-fluoropyrid-3-yl or         2-fluoropyrid-4-yl);     -   halo-alkoxy-pyridyl, e.g. fluoro-methoxy-pyridyl such as         3-fluoro-2-methoxy-pyridyl (in particular         3-fluoro-2-methoxy-pyrid-5-yl);     -   carbamoylpyridyl, especially 2-(carbamoyl)pyridyl (in particular         2-(carbamoyl)pyrid-5-yl); alkyl-substituted carbamoyl, e.g.         methylcarbamoyl, especially 2-(methylcarbamoyl)pyridyl (in         particular 2-(methylcarbamoyl)pyrid-5-yl);     -   piperazinylpyridyl, e.g. 1-piperazinylpyridyl, especially         2-(1-piperazinyl)pyridyl (in particular         2-(1-piperazinyl)pyrid-5-yl); N-alkylpiperazinylpyridyl, such as         N-loweralkylpiperazinylpyridyl, e.g. N-methylpiperazinylpyridyl,         especially 2-(4-methylpiperazin-1-yl)-pyridyl (in particular         2-(4-methylpiperazin-1-yl)-pyrid-5-yl);     -   alkylsulfonamidopyridyl, such as loweralkylsulfonamidopyridyl,         especially methylsulfonamidopyridyl, e.g. 3-(methylsulfonamido)         pyridyl (in particular 3-(methylsulfonamido)-pyridin-5-yl);     -   dialkylsulfonamidopyridyl, such as         diloweralkylsulfonamidopyridyl, especially         dimethylsulfonamidopyridyl, e.g. 3-(dimethylsulfonamido) pyridyl         (in particular 3-(dimethylsulfonamido)-pyridin-5-yl);     -   (alkylsulfonamido)(alkyl)pyridyl such as         (loweralkylsulfonamido)(loweralkyl)pyridyl, especially         (methylsulfonamido)(methyl)pyridyl, e.g.         3-(methylsulfonamido)(methyl)pyridyl (in particular         3-(methylsulfonamido)-2-methylpyridin-5-yl);     -   dialkylsulfonamido(alkyl)pyridyl, such as         diloweralkylsulfonamido(loweralkyl)pyridyl, especially         dimethylsulfonamido(methyl)pyridyl, e.g.         3-(dimethylsulfonamido)(2-methyl)pyridyl (in particular         3-(dimethylsulfonamido)-(2-methyl)-pyridin-5-yl);         3H-tetrazol-5-yl pyridyl, e.g. 2-(3H-tetrazol-5-yl)pyridyl (in         particular 2-(3H-tetrazol-5-yl)pyrid-5-yl);     -   (alkoxy)(alkylcarbonylamino)pyridyl, such as         (loweralkoxy)(loweralkylcarbonylamino)pyridyl, e.g.         (methoxy)(methylcarbonylamino)pyridyl or         (ethoxy)(methylcarbonylamino)pyridyl, especially         2-(methoxy)-3-(methylcarbonylamino)pyridyl or         2-(ethoxy)-3-(methylcarbonylamino)pyridyl (in particular         2-(methoxy)-3-(methylcarbonylamino)pyrid-5-yl or         2-(ethoxy)-3-(methylcarbonylamino)pyrid-5-yl);     -   (alkoxy)(alkylcarbonyl-N-alkylamino)pyridyl, such as         (loweralkoxy)(loweralkylcarbonyl-N-loweralkylamino)pyridyl, e.g.         (methoxy)(methylcarbonyl-N-methylamino)pyridyl or         (ethoxy)(methylcarbonyl-N-methylamino)pyridyl, especially         2-(methoxy)-3-(methylcarbonyl-N-methylamino)pyridyl or         2-(ethoxy)-3-(methylcarbonyl-N-methylamino)pyridyl (in         particular         2-(methoxy)-3-(methylcarbonyl-N-methylamino)pyrid-5-yl or         2-(ethoxy)-3-(methylcarbonyl-N-methylamino)pyrid-5-yl);     -   (alkoxy)(nitro)pyridyl, such as (loweralkoxy)(nitro)pyridyl,         e.g. (methoxy)(nitro)pyridyl, especially         2-(methoxy)-3-(nitro)-pyridyl (in particular         2-(methoxy)-3-(nitro)-pyrid-5-yl);     -   (alkoxy)(cyano) pyridyl, such as (loweralkoxy)(cyano) pyridyl,         e.g. (methoxy)(cyano)pyridyl, especially         2-(methoxy)-3-(cyano)-pyridyl (in particular         2-(methoxy)-3-(cyano)-pyrid-5-yl);     -   (alkoxy)(amino)pyridyl, such as (loweralkoxy)(amino)pyridyl,         e.g. (methoxy)(amino)pyridyl, especially         2-(methoxy)-3-(amino)-pyridyl (in particular         2-(methoxy)-3-(amino)-pyrid-5-yl);     -   (alkoxy)(alkylamino)pyridyl, such as         (loweralkoxy)(alkylamino)pyridyl, e.g.         (methoxy)(ethylamino)pyridyl, especially         2-(methoxy)-3-(ethylamino)pyridyl (in particular         2-(methoxy)-3-(ethylamino)pyrid-5-yl;     -   (alkoxy)(alkylaminocarbonyl)pyridyl, such as         (loweralkoxy)(loweralkylaminocarbonyl)pyridyl, e.g.         (methoxy)(methylaminocarbonyl)pyridyl, especially         2-(methoxy)-3-(methylaminocarbonyl)pyridyl (in particular         2-(methoxy)-3-(methylaminocarbonyl)pyrid-5-yl;     -   (alkoxy)(hydroxycarbonyl)pyridyl, such as         (loweralkoxy)(hydroxycarbonyl)pyridyl, e.g.         (methoxy)(hydroxycarbonyl)pyridyl, especially         2-(methoxy)-3-(hydroxycarbonyl)pyridyl (in particular         2-(methoxy)-3-(hydroxycarbonyl)pyrid-5-yl;     -   pyrimidinyl, in particular pyrimidin-5-yl;     -   di-loweralkylaminopyrimidinyl, e.g. 2- or         4-dimethylaminopyrimidinyl, especially         2-dimethylaminopyrimidinyl (in particular         2-dimethylaminopyrimidin-5-yl);     -   alkoxypyrimidinyl, in particular methoxypyrimidinyl or         ethoxypyrimidinyl, e.g. 2-methoxypyrimidinyl or         2-ethoxypyrimidinyl (in particular 2-methoxypyrimidin-5-yl or         2-ethoxypyrimidin-5-yl);     -   1H-pyrrolo[2,3-b]pyridinyl (in particular         1H-pyrrolo[2,3-b]pyridin-5-yl);     -   1-methyl-1H-pyrrolo[2,3-b]pyridinyl (in particular         1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl);     -   pyrazinyl;     -   pyrazolyl, e.g. pyrazol-4-yl;     -   substituted pyrazolyl, e.g. hydroxyalkylpyrazolyl, especially         1-(2-hydroxy-ethyl)-1H-pyrazolyl (in particular         1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl) or         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl (in         particular         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl);     -   quinolinyl (in particular quinolin-3-yl);     -   2-oxo-2,3-dihydro-1H-indol-5-yl;     -   1-methyl-2,3-dihydro-1H-indol-5-yl;     -   1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl (in particular         1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl,         1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl or         1-(2-methoxyethyl)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl;     -   3H-imidazo[4,5-b]pyridin-6-yl, e.g.         (3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;     -   3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl, e.g.         (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl.

In an embodiment, R³ is selected from:

-   -   pyridyl, 2-methylpyridyl, 3-methylpyridyl, 2-methoxypyridinyl,         3-methoxypyridinyl, 3-ethoxypyridyl, 2-ethoxypyridyl,         2-ethoxypyridyl, 6-(n-propoxy)pyridyl or         3-(iso-propoxy)pyridinyl or 2-(iso-propoxy)pyridinyl,         3-cyclobutoxy-pyridyl, 3-(1,3-difluoropropan-2-yloxy)-pyridyl,         3-(2-fluoroethan-1-yloxy)-pyridyl,         3-(difluoromethyloxy)-pyridyl, 2-cyclopropylmethoxy-pyridyl,         2-methoxymethylpyridyl, 3-methoxymethylpyridyl,         3-(2-methoxy-prop-2-yl)pyridyl, 3-(2-ethoxy-prop-2-yl)pyridyl,         3-(2-methoxyethoxy)pyridyl, 2-(2-methoxyethoxy)pyridyl,         (2-methyl)-(3-(2-methoxyethoxy))pyridyl,         2-benzyloxyethoxypyridyl, 3-benzyloxypropoxy pyridyl,         2-hydroxymethylpyridyl, 3-(1-hydroxyethyl)pyridyl,         3-(3-hydroxypent-3-yl)pyridyl, 3-(2-hydroxyprop-2-yl)pyridyl,         3-(2-hydroxy-1,1-dimethyl-ethyl)pyridyl,         3-(1-hydroxycyclopentyl)-pyridyl,         3-(1,3-difluoro-2-hydroxyprop-2-yl)pyridyl,         3-aminomethylpyridyl, 3-methanesulfonylpyridyl,         2-(2-hydroxyethoxy)-pyridyl, 2-(3-hydroxypropoxy)-pyridyl,         2-methoxycarbonyl-pyridyl, 2-aminopyridyl or 3-aminopyridyl,         2-methylaminopyridyl, 3-methylaminopyridyl, 3-ethylaminopyridyl,         3-isopropylaminopyridyl, 2-dimethylaminopyridyl or         3-dimethylaminopyridyl, 2-diethylaminopyridyl,         3-diethylaminopyridyl, 2-ethylmethylaminopyridyl,         3-ethylmethylaminopyridyl, 2-isopropylmethylaminopyridyl,         3-isopropylmethylaminopyridyl, 3-methylaminopyridyl,         3-(N-methyl-N-cyclobutylamino)pyridyl, 2-methyl-3-amino-pyridyl,         2-ethyl-3-amino-pyridyl, 3-fluoro-2-amino-pyridyl,         2-fluoro-3-amino-pyridyl, 3-chloro-2-amino-pyridyl,         2-chloro-3-amino-pyridyl, 3-fluoro-2-methylamino-pyridyl,         2-fluoro-3-methylamino-pyridyl, 2-fluoro-3-ethylamino-pyridyl,         3-chloro-2-methylamino-pyridyl, 3-chloro-2-ethylamino-pyridyl,         2-chloro-3-ethylamino-pyridyl, 2-fluoro-3-dimethylamino-pyridyl,         3-chloro-2-hydroxymethyl-pyridyl, 3-ethoxy-2-methyl-pyridyl,         3-propoxy-2-methyl-pyridyl, 3-propoxy-2-ethyl-pyridyl,         3-ethoxy-2-ethyl-pyridyl, 3-propoxy-2-methoxy-pyridyl,         3-propoxy-2-ethoxy-pyridyl, 3-methoxy-2-methoxy-pyridyl,         3-ethoxy-2-methoxy-pyridyl,         3-isopropoxy-2-methoxymethyl-pyridyl,         3-methoxy-2-methoxymethyl-pyridyl,         2-methoxy-3-methoxymethyl-pyridyl,         3-methoxy-2-ethoxymethyl-pyridyl,         3-ethoxy-2-methoxymethyl-pyridyl,         3-ethoxy-2-trideuteromethoxymethyl-pyridyl,         3-isopropoxy-2-hydroxymethyl-pyridyl,         3-methoxy-2-hydroxymethyl-pyridyl,         2-methoxy-3-hydroxymethyl-pyridyl,         3-ethoxy-2-hydroxymethyl-pyridyl,         3-(1,3-difluoropropan-2-yloxy)-2-(methyl)-pyridyl,         3-(1,3-difluoropropan-2-yloxy)-2-(hydroxymethyl)-pyridyl,         3-methoxyethoxy-2-hydroxymethyl-pyridyl,         2-methyl-3-ethylamino-pyridyl, 3-methyl-2-methylamino-pyridyl,         2-methyl-3-ethylamino-pyridyl, 2-ethyl-3-isopropylamino-pyridyl,         2-methyl-3-(N-methyl-N-ethylamino)-pyridyl,         2-methyl-3-(N,N-dimethylamino)-pyridyl,         3-azetidin-1-yl-pyridinyl, 2-pyrrolidinyl-1-yl-pyridinyl,         2-(tetrahydro-pyran-4-ylamino)pyridylyl,         6-(3-hydroxy-pyrrolidin-1-yl)-pyridinyl,         6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridinyl,         6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridinyl,         2-(2-hydroxyethylamino)-pyridyl, 2-(methyl)-3-(hydroxy)-pyridyl,         2-(ethyl)-3-(hydroxy)-pyridyl,         2-(hydroxymethyl)-3-(ethylamino)-pyridyl,         2-(hydroxymethyl)-3-(methylamino)-pyridyl,         3-(hydroxymethyl)-2-(methylamino)-pyridyl,         3-(hydroxymethyl)-2-(amino)-pyridyl,         2-(methoxymethyl)-3-(ethylamino)-pyridyl,         2-(methoxymethyl)-3-(methylamino)-pyridyl,         3-(ethoxymethyl)-2-(methylamino)-pyridyl,         3-(ethoxymethyl)-2-(amino)-pyridyl,         3-(methoxymethyl)-2-(amino)-pyridyl,         2-amino-3-trifluoromethyl-pyridyl,         2-methylamino-3-trifluoromethyl-pyridyl,         2-ethylamino-3-trifluoromethyl-pyridyl,         3-trifluoromethyl-2-trideuteromethylamino-pyridyl,         2-trifluoromethylpyridyl, 3-(2-cyanoprop-2-yl)-pyridyl,         3-(1-cyanocyclobutyl)-pyridyl, 2-fluoropyridyl,         3-fluoro-2-methoxy-pyridyl, 2-(carbamoyl)pyridyl,         2-(methylcarbamoyl)pyridyl, 2-(1-piperazinyl)pyridyl,         2-(4-methylpiperazin-1-yl)-pyridyl,         3-(methylsulfonamido)-pyridinyl,         3-(dimethylsulfonamido)-pyridinyl,         3-(methylsulfonamido)-2-methylpyridinyl,         3-(methylsulfonamido)-2-chloro-pyridinyl,         3-(methylsulfonamidomethyl)-pyridinyl,         3-(dimethylsulfonamido)-(2-methyl)-pyridinyl,         2-(3H-tetrazol-5-yl)pyridyl, 3-methylcarbonylaminomethylpyridyl,         2-(chloro)-3-(methylcarbonylamino)pyridyl,         2-(methoxy)-3-(methylcarbonylamino)pyridyl,         2-(ethoxy)-3-(methylcarbonylamino)pyridyl,         2-(methoxy)-3-(methylcarbonyl-N-methylamino)pyridyl,         2-(ethoxy)-3-(methylcarbonyl-N-methylamino)pyridyl,         2-(methoxy)-3-(nitro)-pyridyl, 2-(methoxy)-3-(cyano)-pyridyl,         2-(methoxy)-3-(amino)-pyridyl,         2-(methoxy)-3-(ethylamino)pyridyl,         3-(methoxymethyl)-2-(methylamino)pyridyl,         3-(methoxymethyl)-2-(ethylamino)pyridyl,         2-(methoxy)-3-(methylaminocarbonyl)pyridyl,         3-methylaminocarbonylmethylpyridyl,         2-(amino)-3-(methylaminocarbonyl)pyridyl,         2-(amino)-3-(ethylaminocarbonyl)pyridyl,         2-(amino)-3-(isopropylaminocarbonyl)pyridyl,         2-(amino)-3-(2-methoxyethylaminocarbonyl)pyridyl,         2-(methylamino)-3-(ethylaminocarbonyl)pyridyl,         2-(methoxy)-3-(aminocarbonyl)pyridyl,         2-(methoxy)-3-(hydroxycarbonyl)pyridyl,         3-morpholin-4-ylpyridinyl, (1H-pyrazol-1yl)-pyridinyl,         (2-methyl-1H-imidazol-1-yl)-pyridinyl, pyrimidinyl,         2-dimethylaminopyrimidinyl, 2-methoxypyrimidinyl,         2-ethoxypyrimidinyl, 2,4-dimethoxypyrimidinyl,         2-(methylamino)-4-(methoxy)pyrimidinyl,         2-(ethylamino)-4-(methoxy)pyrimidinyl,         2-(pyrrolidinyl)pyrimidinyl, 2-aminopyrimidinyl,         2-methylaminopyrimidinyl, 2-dimethylaminopyrimidinyl,         1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl,         pyrazinyl, pyrazolyl, 1-(2-hydroxy-ethyl)-1H-pyrazolyl,         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl, quinolinyl,         2-oxo-2,3-dihydro-1H-indolyl, 1-methyl-2,3-dihydro-1H-indolyl,         1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-oneyl,         1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-oneyl,         1-(2-methoxyethyl)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-oneyl,         (3-methyl)-3H-imidazo[4,5-b]pyridinyl,         (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridinyl,         (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridinyl,         (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridinyl,         (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridinyl,         1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl,         1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,         4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,         1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl,         1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl.

In another embodiment, R³ is selected from:

-   -   pyrid-3-yl, 2-methylpyrid-5-yl, 3-methylpyrid-5-yl,         2-methoxypyridin-5-yl, 3-methoxypyridin-5-yl,         3-ethoxypyrid-5-yl, 2-ethoxypyrid-5-yl, 2-ethoxypyrid-4-yl,         6-(n-propoxy)pyrid-3-yl or 3-(iso-propoxy)pyridin-5-yl or         2-(iso-propoxy)pyridin-4-yl, 3-cyclobutoxy-pyrid-5-yl,         3-(1,3-difluoropropan-2-yloxy)-pyrid-5-yl,         3-(2-fluoroethan-1-yloxy)-pyrid-5-yl,         3-(difluoromethyloxy)-pyrid-5-yl,         2-cyclopropylmethoxy-pyrid-5-yl, 2-methoxymethylpyrid-5-yl,         3-methoxymethylpyrid-5-yl, 3-(2-methoxy-prop-2-yl)pyrid-5-yl,         3-(2-ethoxy-prop-2-yl)pyrid-5-yl, 3-(2-methoxyethoxy)pyrid-5-yl,         2-(2-methoxyethoxy)pyrid-5-yl, (2-methyl)-(3-(2-methoxyethoxy))         pyrid-5-yl, 2-benzyloxyethoxypyrid-5-yl,         3-benzyloxypropoxypyrid-5-yl, 2-hydroxymethylpyrid-5-yl,         3-(1-hydroxyethyl)pyrid-5-yl, 3-(3-hydroxypent-3-yl)pyrid-5-yl,         3-(2-hydroxyprop-2-yl)pyrid-5-yl,         3-(2-hydroxy-1,1-dimethyl-ethyl)pyrid-5-yl,         3-(1-hydroxycyclopentyl)-pyrid-5-yl,         3-(1,3-difluoro-2-hydroxyprop-2-yl)pyrid-5-yl,         3-aminomethylpyrid-5-yl, 3-methanesulfonylpyrid-5-yl,         2-(2-hydroxyethoxy)-pyrid-5-yl, 2-(3-hydroxypropoxy)-pyrid-5-yl,         2-methoxycarbonyl-pyrid-5-yl, 2-aminopyrid-5-yl or         3-aminopyrid-5-yl, 2-methylaminopyrid-5-yl,         3-methylaminopyrid-5-yl, 3-ethylaminopyrid-5-yl,         3-isopropylaminopyrid-5-yl, 2-dimethylaminopyrid-5-yl or         3-dimethylaminopyrid-5-yl, 2-diethylaminopyrid-5-yl,         3-diethylaminopyrid-5-yl, 2-ethylmethylaminopyrid-5-yl,         3-ethylmethylaminopyrid-5-yl, 2-isopropylmethylaminopyrid-5-yl,         3-isopropylmethylaminopyrid-5-yl, 3-methylaminopyrid-5-yl,         3-(N-methyl-N-cyclobutylamino)pyrid-5-yl,         2-methyl-3-amino-pyrid-5-yl, 2-ethyl-3-amino-pyrid-5-yl,         3-fluoro-2-amino-pyrid-5-yl, 2-fluoro-3-amino-pyrid-5-yl,         3-chloro-2-amino-pyrid-5-yl, 2-chloro-3-amino-pyrid-5-yl,         3-fluoro-2-methylamino-pyrid-5-yl,         2-fluoro-3-methylamino-pyrid-5-yl,         2-fluoro-3-ethylamino-pyrid-5-yl,         3-chloro-2-methylamino-pyrid-5-yl,         3-chloro-2-ethylamino-pyrid-5-yl,         2-chloro-3-ethylamino-pyrid-5-yl,         2-fluoro-3-dimethylamino-pyrid-5-yl,         3-chloro-2-hydroxymethyl-pyrid-5-yl,         3-ethoxy-2-methyl-pyrid-5-yl, 3-propoxy-2-methyl-pyrid-5-yl,         3-propoxy-2-ethyl-pyrid-5-yl, 3-ethoxy-2-ethyl-pyrid-5-yl,         3-propoxy-2-methoxy-pyrid-5-yl, 3-propoxy-2-ethoxy-pyrid-5-yl,         3-methoxy-2-methoxy-pyrid-5-yl, 3-ethoxy-2-methoxy-pyrid-5-yl,         3-isopropoxy-2-methoxymethyl-pyrid-5-yl,         3-methoxy-2-methoxymethyl-pyrid-5-yl,         2-methoxy-3-methoxymethyl-pyrid-5-yl,         3-methoxy-2-ethoxymethyl-pyrid-5-yl,         3-ethoxy-2-methoxymethyl-pyrid-5-yl,         3-ethoxy-2-trideuteromethoxymethyl-pyrid-5-yl,         3-isopropoxy-2-hydroxymethyl-pyrid-5-yl,         3-methoxy-2-hydroxymethyl-pyrid-5-yl,         2-methoxy-3-hydroxymethyl-pyrid-5-yl,         3-ethoxy-2-hydroxymethyl-pyrid-5-yl,         3-(1,3-difluoropropan-2-yloxy)-2-(methyl)-pyrid-5-yl,         3-(1,3-difluoropropan-2-yloxy)-2-(hydroxymethyl)-pyrid-5-yl,         3-methoxyethoxy-2-hydroxymethyl-pyrid-5-yl,         2-methyl-3-ethylamino-pyrid-5-yl,         3-methyl-2-methylamino-pyrid-5-yl,         2-methyl-3-ethylamino-pyrid-5-yl,         2-ethyl-3-isopropylamino-pyrid-5-yl,         2-methyl-3-(N-methyl-N-ethylamino)-pyrid-5-yl,         2-methyl-3-(N,N-dimethylamino)-pyrid-5-yl,         3-azetidin-1-yl-pyridin-5-yl, 2-pyrrolidinyl-1-yl-pyridin-5-yl,         2-(tetrahydro-pyran-4-ylamino)pyridyl-5-yl,         6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl,         6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl,         6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl,         2-(2-hydroxyethylamino)-pyrid-5-yl,         2-(methyl)-3-(hydroxy)-pyrid-5-yl,         2-(ethyl)-3-(hydroxy)-pyrid-5-yl,         2-(hydroxymethyl)-3-(ethylamino)-pyrid-5-yl,         2-(hydroxymethyl)-3-(methylamino)-pyrid-5-yl,         3-(hydroxymethyl)-2-(methylamino)-pyrid-5-yl,         3-(hydroxymethyl)-2-(amino)-pyrid-5-yl,         2-(methoxymethyl)-3-(ethylamino)-pyrid-5-yl,         2-(methoxymethyl)-3-(methylamino)-pyrid-5-yl,         3-(ethoxymethyl)-2-(methylamino)-pyrid-5-yl,         3-(ethoxymethyl)-2-(amino)-pyrid-5-yl,         3-(methoxymethyl)-2-(amino)-pyrid-5-yl,         2-amino-3-trifluoromethyl-pyrid-5-yl,         2-methylamino-3-trifluoromethyl-pyrid-5-yl,         2-ethylamino-3-trifluoromethyl-pyrid-5-yl,         3-trifluoromethyl-2-trideuteromethylamino-pyrid-5-yl,         2-trifluoromethylpyrid-5-yl, 3-(2-cyanoprop-2-yl)-pyrid-5-yl,         3-(1-cyanocyclobutyl)-pyrid-5-yl, 2-fluoropyrid-3-yl,         2-fluoropyrid-4-yl, 3-fluoro-2-methoxy-pyrid-5-yl,         2-(carbamoyl)pyrid-5-yl, 2-(methylcarbamoyl)pyrid-5-yl,         2-(1-piperazinyl)pyrid-5-yl,         2-(4-methylpiperazin-1-yl)-pyrid-5-yl,         3-(methylsulfonamido)-pyridin-5-yl,         3-(dimethylsulfonamido)-pyridin-5-yl,         3-(methylsulfonamido)-2-methylpyridin-5-yl,         3-(methylsulfonamido)-2-chloro-pyridin-5-yl,         3-(methylsulfonamidomethyl)-pyridin-5-yl,         3-(dimethylsulfonamido)-(2-methyl)-pyridin-5-yl,         2-(3H-tetrazol-5-yl)pyrid-5-yl,         3-methylcarbonylaminomethylpyrid-5-yl,         2-(chloro)-3-(methylcarbonylamino)pyrid-5-yl,         2-(methoxy)-3-(methylcarbonylamino)pyrid-5-yl,         2-(ethoxy)-3-(methylcarbonylamino)pyrid-5-yl,         2-(methoxy)-3-(methylcarbonyl-N-methylamino)pyrid-5-yl,         2-(ethoxy)-3-(methylcarbonyl-N-methylamino)pyrid-5-yl,         2-(methoxy)-3-(nitro)-pyrid-5-yl,         2-(methoxy)-3-(cyano)-pyrid-5-yl,         2-(methoxy)-3-(amino)-pyrid-5-yl,         2-(methoxy)-3-(ethylamino)pyrid-5-yl,         3-(methoxymethyl)-2-(methylamino)pyrid-5-yl,         3-(methoxymethyl)-2-(ethylamino)pyrid-5-yl,         2-(methoxy)-3-(methylaminocarbonyl)pyrid-5-yl,         3-methylaminocarbonylmethylpyrid-5-yl,         2-(amino)-3-(methylaminocarbonyl)pyrid-5-yl,         2-(amino)-3-(ethylaminocarbonyl)pyrid-5-yl,         2-(amino)-3-(isopropylaminocarbonyl)pyrid-5-yl,         2-(amino)-3-(2-methoxyethylaminocarbonyl)pyrid-5-yl,         2-(methylamino)-3-(ethylaminocarbonyl)pyrid-5-yl,         2-(methoxy)-3-(aminocarbonyl)pyrid-5-yl,         2-(methoxy)-3-(hydroxycarbonyl)pyrid-5-yl,         3-morpholin-4-ylpyridin-5-yl, (1H-pyrazol-1-yl)-pyridin-5-yl,         (2-methyl-1H-imidazol-1-yl)-pyridin-5-yl, pyrimidin-5-yl,         2-dimethylaminopyrimidin-5-yl, 2-methoxypyrimidin-5-yl,         2-ethoxypyrimidin-5-yl, 2,4-dimethoxypyrimidin-5-yl,         2-(methylamino)-4-(methoxy)pyrimidin-5-yl,         2-(ethylamino)-4-(methoxy)pyrimidin-5-yl,         2-(pyrrolidinyl)pyrimidin-5-yl, 2-aminopyrimidin-5-yl,         2-methylaminopyrimidin-5-yl, 2-dimethylaminopyrimidin-5-yl,         1H-pyrrolo[2,3-b]pyridin-5-yl,         1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazinyl, pyrazol-4-yl,         1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl,         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl,         quinolin-3-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl,         1-methyl-2,3-dihydro-1H-indol-5-yl,         1,3-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl,         1-ethyl-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl,         1-(2-methoxyethyl)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl,         (3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl,         (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl,         1H-pyrrolo[3,2-b]pyridin-6-yl,         1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl,         1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl,         4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl,         1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl,         1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl.

With the groups of preferred compounds of formula (I) mentioned herein, definitions of substituents from the general definitions mentioned hereinbefore may reasonably be used, e.g., to replace more general definitions with more specific definitions or especially with definitions characterized as being preferred.

A preferred group of compounds of the present invention of formula (I) are those wherein X is O.

Another preferred group of compounds of the present invention of formula (I) are those wherein Y is CH.

Another preferred group of compounds of the present invention of formula (I) are those wherein X is O or S and Y is CH.

Another preferred group of compounds of the present invention of formula (I) are those wherein X is O and Y is CH.

An alternative group of compounds of the present invention of formula (I) are those wherein Y is N.

An alternative group of compounds of the present invention of formula (I) are those wherein X is O or S and Y is N.

An preferred group of compounds of the present invention of formula (I) are those wherein X is O and Y is N.

An embodiment of the present invention includes compounds of formula (I) or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:

-   -   X is O or S;     -   Y is CH or N;     -   R¹ is unsubstituted pyrazolyl or pyrazolyl substituted with one,         two or three substituents, at least one of which is in the         alpha-position, said substituents being independently selected         from lower alkyl; halo; halo lower alkyl, hydroxy lower alkyl,         alkoxy lower alkyl, carbamoyl lower alkyl, hydroxycarbonyl lower         alkyl, dialkylaminocarbonyl lower alkyl, cycloaminocarbonyl         lower alkyl, morpholinecarbonylalkyl, piperazinecarbonyl lower         alkyl or alkyl-substituted piperazinecarbonyl lower alkyl; or     -   R¹ is unsubstituted isoxazolyl or isoxazolyl substituted with         one or two lower alkyl substituents;     -   R² is hydrogen, lower alkyl or lower alkenyl;     -   R³ is unsubstituted phenyl, or phenyl substituted with one or         two groups independently selected from the group consisting of         halo; halo-lower alkyl; hydroxyl; amino; mono or disubstituted         amino; cyclic amino; amino-lower alkyl; lower alkoxy;         hydroxy-lower alkyl; hydroxy lower alkoxy; lower alkyl; cyano;         cyano-lower alkyl; amidino; N-hydroxyamidino; amidino-lower         alkyl; or N-hydroxyamidino-lower alkyl; sulfonyl;         alkyl-substituted sulfonyl; sulfonamide; pyrrolidinesulfonyl;         lower alkyl sulfonyl amino; lower alkyl sulfonylalkandiylamino;         lower alkylsulfonyl-N-lower alkylamino; [1,3]dioxolo;         halo-substituted [1,3]dioxolo; alkoxy carbonyl; carbamoyl;         substituted carbamoyl; heterocycle; heterocyclyl lower alkyl;         heteroaryl or heteroaryl lower alkyl; or     -   R³ is indolyl, 1-methyl-2,3-dihydro-1H-indolyl,         2-oxo-2,3-dihydro-1H-indolyl, pyridyl, pyrimidinyl,         1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl,         pyrazolyl, pyrazinyl, quinolyl,         1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,         1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,         1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl,         2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl,         2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl,         3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl,         2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl,         3-methyl-3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,         1-methyl-1H-pyrrolo[3,2-b]pyridinyl,         1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl,         4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,         1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl and         1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl each of         these heterocycle radicals being unsubstituted or substituted by         one to two radicals selected from the group consisting of halo;         halo-lower alkyl; hydroxyl; amino; mono or disubstituted amino;         cyclic amino; substituted cyclic amino; amino-lower alkyl;         alkylamino-lower alkyl; dialkylamino-loweralkyl;         cycloalkylaminoalkyl; dicycloalkylaminoalkyl;         alkylcycloalkylaminoalkyl; lower alkoxy; cycloalkoxy;         lower-alkoxyalkyl; hydroxy-lower alkyl; hydroxy lower         cycloalkyl; hydroxy lower alkoxy; alkoxy lower alkoxy; lower         alkyl; cyano; cyano-lower alkyl; cyano lower cycloalkyl;         amidino; N-hydroxyamidino; amidino-lower alkyl;         N-hydroxyamidino-lower alkyl; nitro; carboxylic acid;         substituted sulfonyl; sulfonamide; alkylsulfonylamino;         alkylsulfonylalkylamino; acylamino; acyl alkyl amino;         alkylcarbonylaminoalkyl; alkylaminocarbonylalkyl;         alkylcarbonyl-N-alkylamino; [1,3]dioxolo;         substituted[1,3]dioxolo; alkoxy carbonyl; carbamoyl; substituted         carbamoyl; 1H-tetrazolyl; pyrazol; imidazole; triazole;         azetidinyl; pyrrolidinyl; piperazinyl; methylpiperazinyl;         ethylpiperazinyl; triazolonyl; methylimidazolyl or morpholino.     -   A further embodiment of the present invention includes compounds         of formula (I) or pharmaceutically acceptable salts, solvates or         hydrates thereof, wherein:     -   X is O or S;     -   Y is CH or N;     -   R¹ is unsubstituted pyrazolyl or pyrazolyl substituted with one,         two or three substituents, at least one of which is in the         alpha-position, said substituents being independently selected         from lower alkyl; halo; halo lower alkyl, hydroxy lower alkyl,         alkoxy lower alkyl, carbamoyl lower alkyl, hydroxycarbonyl lower         alkyl, dialkylaminocarbonyl lower alkyl, cycloaminocarbonyl         lower alkyl, morpholinecarbonylalkyl, piperazinecarbonyl lower         alkyl or alkyl-substituted piperazinecarbonyl lower alkyl; or     -   R¹ is unsubstituted isoxazolyl or isoxazolyl substituted with         one or two unsubstituted lower alkyl substituents;     -   R² is hydrogen, lower alkyl or lower alkenyl;     -   R³ is selected from phenyl; hydroxyphenyl; methoxyphenyl;         3,4-dimethoxyphenyl; ethoxyphenyl; 3,4-diethoxyphenyl;         iso-propoxyphenyl; methoxy ethoxy-phenyl; 3-methoxy-4-(2-methoxy         ethoxy)-phenyl; fluoro-(iso-propoxy)-phenyl; 3-methoxy-4-hydroxy         phenyl; fluoro-hydroxy-phenyl; hydroxy-fluoroalkyl-phenyl;         2,2-difluoro-benzo[1,3]dioxolo; benzene sulfonamide;         N,N-dimethylbenzenesulfonamide;         3-(pyrrolidine-1-sulfonyl)-phenyl;         N-(phen-3-yl)-methanesulfonamide;         N-methyl-N-phen-3-yl-methanesulfonamide;         3-methanesulfonylphenyl; 3- or 4-benzamide; 3- or         4-N-methyl-benzamide; 3- or 4-N,N-dimethyl-benzamide;         pyrazol-phenyl; imidazol-phenyl; pyridyl; alkylpyridyl;         alkoxypyridyl; cycloalkoxypyridyl; (haloalkoxy)pyridyl;         cycloalkylalkoxypyridyl; alkoxyalkylpyridyl;         alkoxyalkoxypyridyl; (alkyl)(alkoxyalkoxy)pyridyl;         benzyloxyalkoxypyridyl; hydroxyalkylpyridyl;         hydroxycycloalkylpyridyl; hydroxyfluoroalkylpyridyl;         aminoalkylpyridyl; alkyl-sulfonyl pyridyl; hydroxyalkoxypyridyl;         alkoxycarbonylpyridyl; aminopyridyl; alkylaminopyridyl;         dialkylaminopyridyl; cycloalkylaminopyridyl;         (N-alkyl-N-cycloalkylamino)pyridyl; (alkyl)(amino)pyridyl;         (halo)(amino)pyridyl; (halo)(alkylamino)pyridyl;         (halo)(dialkylamino)pyridyl; (halo)(hydroxyalkyl)pyridyl;         (alkoxy)(alkyl)pyridyl; (alkoxy)(alkoxy)pyridyl;         (alkoxy)(alkoxyalkyl)pyridyl;         (alkoxy)(deuteroalkoxy-alkyl)pyridyl;         (alkoxy)(hydroxyalkyl)pyridyl; (haloalkoxy)(alkyl)pyridyl;         (haloalkoxy)(hydroxyalkyl)pyridyl;         (alkoxyalkoxy)(hydroxyalkyl)pyridyl; (alkyl)(alkylamino)pyridyl;         (alkyl)(di-alkylamino)pyridyl; cycloaminopyridyl; cyclic         ether-substituted amino-pyridyl; hydroxy-cycloaminopyridyl;         loweralkoxy-cycloaminopyridyl; hydroxyalkylaminopyridyl;         (alkyl)(hydroxy)pyridyl; (hydroxyalkyl)(alkylamino)pyridyl;         (hydroxyalkyl)(amino)pyridyl; (alkoxyalkyl)(alkylamino)pyridyl;         (alkoxyalkyl)(amino)pyridyl; amino-haloloweralkyl-pyridyl;         alkylamino-haloalkyl-pyridyl;         haloalkyl-deuteroloweralkylamino-pyridyl; haloalkylpyridinyl;         cyanoalkylpyridinyl; cyanocycloalkylpyridinyl; halopyridyl;         halo-alkoxy-pyridyl; carbamoylpyridyl; alkyl-substituted         carbamoylpyridyl; piperazinylpyridyl; N-alkylpiperazinylpyridyl;         alkylsulfonamidopyridyl; dialkylsulfonamidopyridyl;         (alkylsulfonamido)(alkyl)pyridyl;         (alkylsulfonamido)(halo)pyridyl; (alkylsulfonamidoalkyl)pyridyl;         dialkylsulfonamido(alkyl)pyridyl; 3H-tetrazol-5-yl pyridyl;         alkylcarbonylaminoalkylpyridyl;         (halo)(alkylcarbonylamino)pyridyl;         (alkoxy)(alkylcarbonylamino)pyridyl;         (alkoxy)(alkylcarbonyl-N-alkylamino)pyridyl;         (alkoxy)(nitro)pyridyl; (alkoxy)(cyano)pyridyl;         (alkoxy)(amino)pyridyl; (alkoxy)(alkylamino)pyridyl;         (alkoxyalkyl)(alkylamino)pyridyl;         (alkoxy)(alkylaminocarbonyl)pyridyl;         (alkoxyalkyl)(alkylamino)pyridyl;         (amino)(alkylaminocarbonyl)pyridyl;         (amino)(alkoxyalkylaminocarbonyl)pyridyl;         (alkylamino)(alkylaminocarbonyl)pyridyl;         (alkoxy)(aminocarbonyl)pyridyl;         (alkoxy)(hydroxycarbonyl)pyridyl; morpholinylpyridinyl;         (1H-pyrazolyl)-pyridinyl;         loweralkylsubstituted(1H-imidazol-1-yl)-pyridinyl; pyrimidinyl;         di-loweralkylaminopyrimidinyl; alkoxypyrimidinyl;         di-alkoxypyrimidinyl; (alkylamino)(alkoxy)pyrimidinyl;         cycloaminopyrimidinyl; aminopyrimidinyl; alkylaminopyrimidinyl;         dialkylaminopyrimidinyl; 1H-pyrrolo[2,3-b]pyridinyl;         1-methyl-1H-pyrrolo[2,3-b]pyridinyl; pyrazinyl; pyrazolyl;         hydroxyalkylpyrazolyl;         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl; quinolinyl;         2-oxo-2,3-dihydro-1H-indol-5-yl;         1-methyl-2,3-dihydro-1H-indol-5-yl;         1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl;         3H-imidazo[4,5-b]pyridin-6-yl;         (3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl;         (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl;         H-pyrrolo[3,2-b]pyridin-6-yl;         1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl;         2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl;         1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl;         3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl;         4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl;         1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl;         2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl;         1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl.

An embodiment of the present invention includes compounds of formula (I) or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:

-   -   X is O or S;     -   Y is CH or N;     -   R¹ is unsubstituted pyrazolyl or pyrazolyl substituted with one,         two or three substituents, at least one of which is in the         alpha-position, said substituents being independently selected         from lower alkyl; halo; halo lower alkyl, hydroxy lower alkyl,         alkoxy lower alkyl, carbamoyl lower alkyl, hydroxycarbonyl lower         alkyl, dialkylaminocarbonyl lower alkyl, cycloaminocarbonyl         lower alkyl, morpholinecarbonylalkyl or piperazinecarbonyl lower         alkyl;     -   R² is hydrogen or lower alkyl;     -   R³ is unsubstituted phenyl, or phenyl substituted with one or         two groups independently selected from the group consisting of         halo; halo-lower alkyl; hydroxyl; amino; mono or disubstituted         amino; cyclic amino; amino-lower alkyl; lower alkoxy;         hydroxy-lower alkyl; hydroxy lower alkoxy; lower alkyl; cyano;         cyano-lower alkyl; amidino; N-hydroxyamidino; amidino-lower         alkyl; or N-hydroxyamidino-lower alkyl; sulfonyl;         alkyl-substituted sulfonyl; sulfonamide; pyrrolidinesulfonyl;         [1,3]dioxolo; halo-substituted [1,3]dioxolo; alkoxy carbonyl;         carbamoyl; substituted carbamoyl; heterocycle; heterocyclyl         lower alkyl; heteroaryl or heteroaryl lower alkyl; or     -   R³ is indolyl, 2,3-dihydro-1H-indol-5-yl,         1-methyl-2,3-dihydro-1H-indol-5-yl,         2-oxo-2,3-dihydro-1H-indol-5-yl, pyridyl, pyrimidinyl,         1H-pyrrolo[2,3-b]pyridin-5-yl,         1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazolyl, pyrazol-4-yl,         pyrazinyl, quinolyl, quinol-3-yl,         1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl,         3H-imidazo[4,5-b]pyridin-6-yl,         3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl each independently being         unsubstituted or substituted by one or two radicals         independently selected from the group consisting of halo;         halo-lower alkyl; hydroxyl; amino; mono or disubstituted amino;         cyclic amino; amino-lower alkyl; lower alkoxy; lower alkoxy         lower alkyl; hydroxy-lower alkyl; hydroxy lower alkoxy; lower         alkyl; cyano; cyano-lower alkyl; amidino; N-hydroxyamidino;         amidino-lower alkyl; or N-hydroxyamidino-lower alkyl; sulfonyl;         alkyl-substituted sulfonyl; sulfonamide; pyrrolidine-1-sulfonyl;         [1,3]dioxolo; halo substituted [1,3]dioxolo; alkoxy carbonyl;         carbamoyl; aminocarbonylalkyl; N-mono-substituted         aminocarbonylalkyl; N-di-substituted aminocarbonylalkyl;         3H-tetrazolyl, pyrazol, heterocyclyl lower alkyl, heteroaryl or         heteroaryl lower alkyl.

A further embodiment of the present invention includes compounds of formula (I) or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:

-   -   X is O or S;     -   Y is CH or N;     -   R¹ is unsubstituted pyrazolyl or pyrazolyl substituted with one,         two or three substituents, at least one of which is in the         alpha-position, said substituents being independently selected         from lower alkyl; halo; halo lower alkyl, hydroxy lower alkyl,         alkoxy lower alkyl, carbamoyl lower alkyl, hydroxycarbonyl lower         alkyl, dialkylaminocarbonyl lower alkyl, cycloaminocarbonyl         lower alkyl, morpholinecarbonylalkyl or piperazinecarbonyl lower         alkyl;     -   R² is hydrogen or lower alkyl;     -   R³ is selected from phenyl; hydroxyphenyl; methoxyphenyl;         3,4-dimethoxyphenyl; ethoxyphenyl; 3,4-diethoxyphenyl; methoxy         ethoxy-phenyl; 3-methoxy-4-(2-methoxy ethoxy)-phenyl;         3-methoxy-4-hydroxy phenyl; fluoro-hydroxy-phenyl;         hydroxy-fluoroalkyl-phenyl; 2,2-difluoro-benzo[1,3]dioxolo;         benzene sulfonamide; 3-(pyrrolidine-1-sulfonyl)-phenyl;         N-(phen-3-yl)-methanesulfonamide;         N-methyl-N-phen-3-yl-methanesulfonamide;         3-methanesulfonylphenyl; 3- or 4-benzamide; 3- or         4-N-methyl-benzamide; 3- or 4-N,N-dimethyl-benzamide;         pyrazol-phenyl; imidazol-phenyl; pyridyl; alkylpyridyl;         alkoxypyridyl; cycloalkylalkoxypyridyl; alkoxyalkylpyridyl;         alkoxyalkoxypyridyl, benzyloxyalkoxypyridyl,         hydroxyalkylpyridyl; alkyl-sulfonyl pyridyl;         hydroxyalkoxypyridyl; alkoxycarbonylpyridyl; aminopyridyl;         alkylaminopyridyl; dialkylaminopyridyl; (alkyl)(amino)pyridyl;         (alkoxy)(alkyl)pyridyl; (alkoxy)(alkoxy)pyridyl;         (alkyl)(alkylamino)pyridyl; (alkyl)(di-alkylamino)pyridyl;         cycloaminopyridyl; hydroxyalkylaminopyridyl;         amino-haloloweralkyl-pyridyl; haloalkylpyridinyl; halopyridyl;         halo-alkoxy-pyridyl; carbamoylpyridyl; alkyl-substituted         carbamoylpyridyl; piperazinylpyridyl; N-alkylpiperazinylpyridyl;         alkylsulfonamidopyridyl; dialkylsulfonamidopyridyl;         (alkylsulfonamido)(alkyl)pyridyl;         dialkylsulfonamido(alkyl)pyridyl; 3H-tetrazol-5-yl pyridyl;         (alkoxy)(alkylcarbonylamino)pyridyl;         (alkoxy)(alkylcarbonyl-N-alkylamino)pyridyl;         (alkoxy)(nitro)pyridyl; (alkoxy)(cyano) pyridyl;         (alkoxy)(amino)pyridyl; (alkoxy)(alkylamino)pyridyl;         (alkoxy)(alkylaminocarbonyl)pyridyl;         (alkoxy)(hydroxycarbonyl)pyridyl; pyrimidinyl;         di-loweralkylaminopyrimidinyl; alkoxypyrimidinyl;         1H-pyrrolo[2,3-b]pyridinyl; 1-methyl-1H-pyrrolo[2,3-b]pyridinyl;         pyrazinyl; pyrazolyl; hydroxyalkylpyrazolyl;         1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl; quinolinyl;         2-oxo-2,3-dihydro-1H-indol-5-yl;         1-methyl-2,3-dihydro-1H-indol-5-yl;         1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl;         3H-imidazo[4,5-b]pyridin-6-yl;         (3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl;         3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl;         (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl.

Most preferred is a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, as exemplified hereinbelow under “Examples”.

The present invention is further directed to a method of treating a protein kinase dependent disease comprising administering a compound of formula (I), where the disease to be treated is a proliferative disease, preferably a benign or especially malignant tumor, more preferably carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, lymphomas, a mammary carcinoma or a leukemia, and including proliferative diseases such as tumor diseases, leukaemias and myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia, basal cell carcinoma, squamous cell carcinoma and actinic keratosis and other benign hyperproliferative skin disorders caused by inflammation such as psoriasis or as a result of dysregulation of fibroblasts such as skin fibrosis, scleroderma or keloids.

Other diseases include Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome or diseases in which the PI3K/PKB pathway is aberrantly activated.

Most preferred is the use in accordance with the present invention of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, as exemplified hereinbelow under “Examples”.

The compounds of formula (I) that inhibit the protein or lipid kinase activities mentioned, especially mTOR Ser/Thr kinase activity and/or class I PI3 kinases activity, may therefore be useful in the treatment of protein or lipid kinase dependant diseases, especially diseases depending on class I and/or class IV PI3 kinases, for example, PI3Kalpha, PI3 Kbeta, PI3 Kdelta, PI3 Kgamma and/or mTOR, or one or more of the individual kinase members thereof, including other PI3-kinases such as DNA-PK, ATM, ATR, hSMG-1 and Vps34 or any combination of two or more of the mentioned kinases.

Protein or lipid kinase dependent diseases are especially proliferative diseases, a benign or especially malignant tumor, a carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially gastric tumors), ovaries, colon, rectum, prostate, pancreas, lung, vagina, thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, or a tumor of the neck and head, other diseases such as Cowden syndrome, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway is aberrantly activated, an epidermal hyperproliferation, especially psoriasis, prostate hyperplasia, a neoplasia, especially of epithelial character, preferably mammary carcinoma or squamous cell carcinoma, or a leukemia. The compounds desirably are able to bring about the regression of tumors and to prevent the formation of tumor metastases and the growth of (also micro) metastases. In addition, they may be used in epidermal hyperproliferation, e.g., psoriasis; in prostate hyperplasia; in the treatment of neoplasias, especially of epithelial character, e.g., mammary carcinoma; in leukemias; and in basal cell carcinoma, squamous cell carcinoma and actinic keratosis. It may also be possible to use the compounds of formula (I) in the treatment of diseases of the immune system insofar as several or, especially, individual lipid kinases and/or (further) serine/threonine protein kinases are involved.

The compounds of the formula (I) can be prepared according to the following methods:

A compound of formula (I) is converted into a compound of formula (I) by known in the art chemical reactions such as protecting group deprotection, e.g. tert-butyloxycarbonyl (boc) group deprotection with TFA, neat or in presence of a solvent such as a polyhalogeneated alkane, e.g. dichloromethane, at a temperature between 0° C. to 40° C.; functional group substitution e.g. alkylation of a hydroxyl group to form an alkoxy group by treatment with a strong based such as metal hydride, e.g. sodium hydride, in an aprotic solvent, e.g. THF or dimethylformamide, followed by addition of an alkylhalide, e.g. methyliodide, at a temperature between −20° C. and 40° C.; or functional group modification e.g. conversion of a carbonyl to a thiocarbonyl by treatment with Lawesson's reagent in a cyclyether solvent, e.g. dioxane at a temperature between 60° C. and 120° C. or at reflux.

A compound of formula (I) wherein Y=CH is prepared by reacting a compound of the formula (II)

wherein

-   -   Hal refers to halogen preferably bromine; and     -   X, R¹, R², R⁴, R⁵ and R⁶ are as defined herein above;         A: with a boronic acid of the formula III

R_(a)—B(OH)₂  (III)

-   -   or a boronate ester such as of formula IIIa

wherein R³ is as defined for a compound of the formula (I), in the presence of a base and a catalyst in a suitable solvent; to provide a compound of formula (I) or, B: with a bis(diborane), such as bis(pinacolato)-diborane, in the presence of a base and a catalyst in a suitable solvent, to provide an intermediate of formula IIA:

followed by reaction of the compound according to formula (IIa) with a compound according to formula (IIIb):

R³-Hal  (IIIb)

wherein Hal refers to halogen preferably bromine, in the presence of a base and a catalyst in a suitable solvent; to provide a compound of formula (I); where the above starting compounds II, IIa, III, IIIa and IIIb may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible; any protecting groups in a protected derivative of a compound of the formula I are optionally removed; and if desired, transforming an obtainable compound of formula (I) into a different compound of formula (I), or a N-oxide thereof, transforming a salt of an obtainable compound of formula (I) into the free compound or a different salt, or an obtainable free compound of formula (I) into a salt; and/or separating an obtainable mixture of isomers of compounds of formula (I) into the individual isomers.

In the following, more detailed description of the preferred process conditions, X, R¹, R², R³, R⁴, R⁵ and R⁶ have the meanings given herein for compounds of the formula (I), if not indicated otherwise.

Conversion of R² from H to a substituent different from H as defined above for R² can be achieved by treating compound of formula (I) or (II) in presence of a strong base in a suitable solvent and subsequent adjunction of a halogenated reagent Hal-R² wherein Hal refers to halogen preferably iodine or bromine, e.g. methyliodide.

A compound of formula (II) is prepared by reacting a compound of formula (IV)

with phosgene or trichloromethyl chloroformate in a suitable solvent in presence of a base wherein

-   -   R¹, R⁴, R⁵ and R⁶ are as mentioned for a compound of the formula         (I).

A compound of the formula (IV) is prepared by reduction of a compound of the formula (V)

wherein the substituents and symbols are defined as for compounds of the formula (I) in the presence of an appropriate catalyst, e.g., a skeleton based catalyst, such as Raney-Ni with hydrogen in an appropriate solvent, e.g., an alcohol and or a cycloalkylether, such as methanol and/or tetrahydrofurane; at preferred temperatures e.g. between 0° C. and 50° C., e.g., at RT.

A compound of formula (V) is preferably prepared by reacting a compound of the formula (VI)

wherein

-   -   Q is halo, especially chloro; and     -   the other moieties and symbols have the meanings indicated for         compounds of the formula (I) with a compound of the formula         (VII)

R₁—NH₂  (VII),

-   -   wherein R₁ is as defined for a compound of the formula (I), in         the presence of a base such as a tertiaryamine, e.g.         1,2,2,6,6-pentamethylpiperidine, in an appropriate solvent;         preferably a polar aprotic solvent such as dimethylacetamide, at         preferred temperatures between 20° C. and 120° C. temperature of         the reaction mixture, e.g., between 20° C. and 70° C.

A compound of the formula (VI) can be prepared by reacting a compound of the formula (VIII)

wherein the moieties and symbols have the meanings indicated for a compound of the formula (I), with an inorganic acid halogenide, especially POCl₃ (preferably without solvent) at elevated temperatures, e.g., between 100° C. and 150° C. or under reflux.

A compound of the formula (VIII) is known in the art, can be synthesized according to methods known in the art and/or is commercially-available. For example, it can be synthesized by reacting a compound of the formula (IX)

wherein the moieties and symbols have the meanings indicated for a compound of the formula (I) (x is preferably zero), with nitric acid (aqueous) at a preferred temperature between 50° C. and 100° C., e.g., at 85° C.

A compound of the formula (VIII), can alternatively be synthesized by reacting a compound of the formula (X)

wherein the moieties and symbols have the meanings indicated for a compound of the formula (I), with an anhydride of a carbonic acid, especially acetic anhydride, preferably in the presence of an alkali metal salt of a carboxylic acid, e.g., potassium acetate, at a preferred temperature between 50° C. and 150° C., e.g., at ca. 100-140° C.

A compound of the formula (X) can be obtained, e.g., by converting a compound of the formula (XI)

to the corresponding compound of the formula (X) by reacting nitromethane in the presence of an alkali metal hydroxide, especially sodium hydroxide, at preferred temperatures between approximately 0° C. and 60° C., e.g., between 0° C. and RT; then pouring the product under cooling to approximately 0° C. into concentrated HCl and adding the compound of the formula (XI) and further concentrated HCl, subsequently allowing for further reaction at preferred temperatures between 00° C. and RT to result in the corresponding compound of formula (X).

A compound of formula (I) wherein Y=N is prepared in two steps by saponification of the ester group by treatment with a base such as an alkali metal hydroxide, e.g. lithium hydroxide in a solvent such as wet cycloaklylether, e.g. dioxane/water, at a temperature between 20° C. and 100° C., preferably between 30° C. and 60° C., a compound of the formula (XII)

wherein

-   -   R¹, R³, R⁴, R⁵ and R⁶ are as defined herein above and R is         unsubstituted or substituted lower alkyl, e.g. ethyl;

The freed intermediate obtained after neutralization of the reaction mixture with an acid, such as a mineral acid, e.g. hydrochloric acid, and evaporation to dryness is converted by a Cursius rearrangement to compound of formula (I) via in situ formation of the acylazide intermediate by treatment with diphenylphosphorylazide in an aprotic solvent, such as polar aprotic and/or polar protic, e.g. toluene/N-methylpyrrolidinone, in presence of a base, such as a tertiaryamine, e.g. triethylamine, at temperature between 60° C. and 120° C., e.g. between 80° C. and 110° C.; the isocyanato intermediate spontaneously cyclized to form compound of formula (I) in the reaction conditions.

A compound of formula (XII) is preferably prepared by reacting a compound of the formula (XIII)

wherein

-   -   Q is halo, especially chloro; and     -   the other moieties have the meanings indicated for compounds of         the formula (I), and R is unsubstituted or substituted lower         alkyl, e.g. ethyl, with a compound of the formula (VII)

R₁—NH₂  (VII),

wherein R₁ is as defined for a compound of the formula (I), in the presence of a base such as a tertiaryamine, e.g. 1,2,2,6,6-pentamethylpiperidine, in an appropriate solvent; preferably a polar aprotic solvent such as dimethylacetamide, at preferred temperatures between 20° C. and 120° C. temperature of the reaction mixture, e.g., between 20° C. and 70° C.

A compound of formula (XIII) is preferably prepared by reacting a compound of the formula (XIV)

wherein the moieties have the meanings indicated for a compound of the formula (I) and R is unsubstituted or substituted lower alkyl, e.g. ethyl, with an inorganic acid halogenide, especially POCl₃ (preferably without solvent) at elevated temperatures, e.g., between 100° C. and 150° C. or under reflux.

A compound of formula (XIV) is preferably prepared by reacting a compound of the formula (XV)

wherein the moieties have the meanings indicated for a compound of the formula (I) with a compound of formula (XVI)

R and R′ being selected independently from unsubstituted or substituted alkyl, e.g. being both ethyl; in a solvent and pressure condition, e.g. xylene in a seal tube, allowing reaction at a temperature between 150° C. and 300° C., e.g. between 220° C. and 250° C.

A compound of formula (XV) is known in the art and can be prepared by reduction of a compound of the formula (XVII)

wherein the moieties have the meanings indicated for a compound of the formula (I) with a compound of formula (XVI) in the presence of an appropriate catalyst, e.g., a skeleton based catalyst, such as Raney-Ni with hydrogen in an appropriate solvent, e.g., an alcohol and or a cycloalkylether, such as methanol and/or tetrahydrofurane; at preferred temperatures e.g. between 0° C. and 50° C., e.g., at RT.

A compound of formula (XVII) is known in the art and can be prepared by reacting a compound of formula (XVIII)

with a boronic acid of the formula III

R₃—B(OH)₂  (III)

-   -   or a boronate ester such as of formula IIIa

wherein R₃ is as defined for a compound of the formula (I), in the presence of a base and a catalyst in a suitable solvent.

Other starting materials are either known in the art, can be prepared according to methods that are known in the art, e.g., in analogy to the methods described hereinabove or in the examples, and/or are commercially-available.

The present invention relates also to novel starting materials and/or intermediates and to processes for their preparation. The starting materials used and the reaction conditions selected are preferably those that result in the compounds described as being preferred.

Other starting materials are either known in the art, can be prepared according to methods that are known in the art, e.g., in analogy to the methods described hereinabove or in the examples, and/or are commercially-available.

The present invention relates also to novel starting materials and/or intermediates and to processes for their preparation. The starting materials used and the reaction conditions selected are preferably those that result in the compounds described as being preferred.

Salts of compounds of formula (I) having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of formula (I) having acid groups may be formed, e.g., by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethylhexanoic acid; with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate; with corresponding calcium compounds or with ammonia a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of formula (I) are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula (I) containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralization of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.

Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, e.g., by treatment with suitable acids; and acid addition salts, e.g., by treatment with a suitable basic agent.

Mixtures of isomers obtainable according to the invention can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, e.g., by partitioning between polyphasic solvent mixtures, recrystallization and/or chromatographic separation, e.g., over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column; and racemates can be separated, e.g., by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, e.g., by means of fractional crystallization, or by chromatography over optically active column materials.

Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, re-crystallization and the like.

Additional Process Steps

In the additional process steps, carried out as desired, functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected, e.g., by one or more protecting groups. The protecting groups are then wholly or partly removed according to one of the known methods.

Protecting groups, and the manner in which they are introduced and removed are described, e.g., Protective Groups in Organic Chemistry, Plenum Press, London, N.Y. (1973); Methoden der organischen Chemie, Houben-Weyl, 4^(th) Edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart (1974); and Theodora W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, NY (1981). A characteristic of protecting groups is that they can be removed readily, i.e., without the occurrence of undesired secondary reactions, e.g., by solvolysis, reduction, photolysis or alternatively under physiological conditions.

The end products of formula (I) may however also contain substituents that can also be used as protecting groups in starting materials for the preparation of other end products of formula (I). Thus, within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of formula (I) is designated a “protecting group”, unless the context indicates otherwise.

General Process Conditions

The following applies in general to all processes mentioned hereinbefore and hereinafter, while reaction conditions specifically mentioned above or below are preferred:

All the above-mentioned process steps can be carried out under reaction conditions that are known per se, preferably those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, preferably solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, e.g., ion exchangers, such as cation exchangers, e.g., in the H⁺ form; depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, e.g., in a temperature range of from about −100° C. to about 190° C.; preferably from approximately −80° C. to approximately 150° C., e.g., at from −80° C. to −60° C. at RT, at from −20° C. to 40° C. or at reflux temperature; under atmospheric pressure or in a closed vessel, where appropriate under pressure and/or in an inert atmosphere, e.g., under an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, e.g., diastereoisomers or enantiomers; or into any desired mixtures of isomers, e.g., racemates or mixtures of diastereoisomers, e.g., analogously to the methods described under “additional process steps”.

The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, e.g., water; esters, such as lower alkyl-lower alkanoates, e.g., ethyl acetate; ethers, such as aliphatic ethers, e.g., diethyl ether; or cyclic ethers, e.g., tetrahydrofuran or dioxane; liquid aromatic hydrocarbons, such as benzene or toluene; alcohols, such as methanol, ethanol or 1- or 2-propanol; nitriles, such as acetonitrile; halogenated hydrocarbons, such as methylene chloride or chloroform; acid amides, such as dimethylformamide or dimethyl acetamide; bases, such as heterocyclic nitrogen bases, e.g., pyridine or N-methylpyrrolidin-2-one; carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, e.g., acetic anhydride; cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane; or mixtures of those solvents, e.g., aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, e.g., by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, e.g., include the solvent used for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, e.g., in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ. In the process of the present invention those starting materials are preferably used which result in new compounds of formula (I) described at the beginning as being especially valuable. Special preference is given to reaction conditions that are analogous to those mentioned in the examples.

Pharmaceutical Compositions

The invention relates also to pharmaceutical compositions comprising a compound of formula (I), to their use in the therapeutic (in a broader aspect of the invention also prophylactic) treatment or a method of treatment of a lipid or protein kinase dependent disease, especially the preferred diseases mentioned above, to the compounds for said use and to the preparation of pharmaceutical preparations, especially for said uses.

The present invention also relates to pro-drugs of a compound of formula (I) that convert in vivo to the compound of formula (I) as such. Any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding pro-drugs of the compound of formula (I), as appropriate and expedient. The pharmacologically acceptable compounds of the present invention may be used, e.g., for the preparation of pharmaceutical compositions that comprise an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as active ingredient together or in admixture with a significant amount of one or more inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.

The invention relates also to a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human, e.g., lymphocytes), for the treatment or, in a broader aspect of the invention, prevention of (=prophylaxis against) a disease that responds to inhibition of protein kinase activity, comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective for said inhibition, especially the in, together with at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions according to the invention are those for enteral, such as nasal; rectal or oral; parenteral, such as intramuscular or intravenous; or topical, such as dermal administration to warm-blooded animals (especially a human), that comprise an effective dose of the pharmacologically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

The invention relates also to a method of treatment for a disease that responds to inhibition of a lipid or protein kinase, which comprises administering an (against the mentioned disease) prophylactically or especially therapeutically effective amount of a compound of formula (I) according to the invention, especially to a warm-blooded animal, e.g., a human, that, on account of one of the mentioned diseases, requires such treatment.

The dose of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals, e.g., humans of approximately 70 kg body weight, is preferably from approximately 3 mg to approximately 10 g, more preferably from approximately 10 mg to approximately 1.5 g, most preferably from about 100 mg to about 1000 mg/person/day, divided preferably into 1-3 single doses which may, e.g., be of the same size. Usually, children receive half of the adult dose.

The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, e.g., in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, e.g., by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.

Solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions, are preferably used, it being possible, e.g., in the case of lyophilized compositions that comprise the active ingredient alone or together with a carrier, e.g., mannitol, for such solutions or suspensions to be produced prior to use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, e.g., preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and/or buffers; and are prepared in a manner known per se, e.g., by means of conventional dissolving or lyophilizing processes. The said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable, synthetic or semi-synthetic oils customary for injection purposes. There may be mentioned as such especially liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8-22 carbon atoms, especially from 12-22 carbon atoms, e.g., lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, e.g., oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with the addition of antioxidants, e.g., vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydroxy, e.g., a mono-, di- or tri-hydroxy; alcohol, e.g., methanol, ethanol, propanol, butanol or pentanol; or the isomers thereof, but especially glycol and glycerol. The following examples of fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), “Miglyol 812” (triglyceride of saturated fatty acids with a chain length of C₈-C₁₂, Hüls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.

The injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.

Suitable carriers are especially fillers, such as sugars, e.g., lactose, saccharose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g., tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes using, e.g., corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and/or, if desired, disintegrators, such as the above-mentioned starches; and/or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, e.g., silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate; and/or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide; or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Capsules are dry-filled capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules may comprise the active ingredient in the form of granules, e.g., with fillers, such as lactose; binders, such as starches; and/or glidants, such as talc or magnesium stearate; and if desired with stabilizers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added. Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, e.g., for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for topical administration can be obtained by combining the active ingredient with a liquid carrier (e.g. an aqueous liquid carrier) to dissolve or disperse the active, together with further optional formulating ingredients such as solvents/solubilisers, gelling agents, oils, stabilisers, buffers and preservatives to provide for example a solution, lotion, cream, gel or ointment. The pharmaceutical compositions for topical administration may be provided, for example, for dermal application. The pharmaceutical compositions for topical administration may comprise from approximately 0.1% to approximately 2% of active ingredient, the active ingredient being especially a compound of formula (I), in particular, a compound described in the individual examples herein.

Compounds of the invention display particularly high solubilities in organic solvents. The compounds of the invention are thus particularly useful for topical administration, e.g. to a mammal such as a human, e.g. to the skin of said mammal. The compounds are thus useful for formulation into compositions suitable for topical administration. Compounds displaying high solubility thus provide an advantage for topical administration over compounds having a lower solubility.

The solubility of certain compounds was determined in the organic solvents PEG400, propyleneglycol and ethanol. The results are provided in the following table, showing high solubilities of the specified compounds, demonstrating that those compounds are particularly suitable for formulation into compositions for topical administration.

Example Example Example Example 4.1 58.1 84.1 191.1 Solubility Solubility Solubility Solubility Excipient [mg/mL] [mg/mL] [mg/mL] [mg/mL] PEG400 >20 >26 >19 >23 Propyleneglycol >20 >24 >20 >19 Ethanol abs. 4.11 >22 >21 >24

Combinations

A compound of the formula (I) may also be used to advantage in combination with each other or in combination with other therapeutic agents, especially other antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds, which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMODAL®); and leucovorin.

The term “aromatase inhibitor”, as used herein, relates to a compound which inhibits the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark AROMASIN. Formestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.

The term “anti-estrogen”, as used herein, relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g., under the trademark EVISTA. Fulvestrant can be formulated as disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g., under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors.

The term “anti-androgen”, as used herein, relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g., as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist”, as used herein, includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin is disclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOLADEX. Abarelix can be formulated, e.g., as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor”, as used herein, includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR. Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor”, as used herein, includes, but is not limited to, the anthracyclines, such as doxorubicin, including liposomal formulation, e.g., CAELYX; daunorubicin; epirubicin; idarubicin; nemorubicin; the anthraquinones mitoxantrone and losoxantrone; and the podophillotoxines etoposide and teniposide. Etoposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ETOPOPHOS. Teniposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark VM 26-BRISTOL. Doxorubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN. Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS. Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOVANTRON.

The term “microtubule active agent” relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to, taxanes, e.g., paclitaxel and docetaxel; vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate; vincristine, especially vincristine sulfate and vinorelbine; discodermolides; cochicine; and epothilones and derivatives thereof, e.g., epothilone B or D or derivatives thereof. Paclitaxel may be administered, e.g., in the form as it is marketed, e.g., TAXOL. Docetaxel can be administered, e.g., in the form as it is marketed, e.g., under the trademark TAXOTERE. Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark VINBLASTIN R.P. Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMISTIN. Discodermolide can be obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also included are epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferred are epothilone A and/or B.

The term “alkylating agent”, as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof. It further especially includes suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limited to, 5-fluorouracil or 5-FU; capecitabine; gemcitabine; DNA demethylating agents, such as 5-azacytidine and decitabine; methotrexate and edatrexate; and folic acid antagonists, such as pemetrexed. Capecitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark XELODA. Gemcitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark GEMZAR. Also included is the monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g., under the trademark HERCEPTIN.

The term “platin compound”, as used herein, includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds”, as used herein, includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,

-   -   a) compounds targeting, decreasing or inhibiting the activity of         the platelet-derived growth factor-receptors (PDGFR), such as         compounds which target, decrease or inhibit the activity of         PDGFR, especially compounds which inhibit the PDGF receptor,         e.g., a N-phenyl-2-pyrimidine-amine derivative, e.g., imatinib,         SU101, SU6668 and GFB-111;     -   b) compounds targeting, decreasing or inhibiting the activity of         the fibroblast growth factor-receptors (FGFR);     -   c) compounds targeting, decreasing or inhibiting the activity of         the insulin-like growth factor receptor I (IGF-IR), such as         compounds which target, decrease or inhibit the activity of         IGF-IR, especially compounds which inhibit the IGF-IR receptor,         such as those compounds disclosed in WO 02/092599;     -   d) compounds targeting, decreasing or inhibiting the activity of         the Trk receptor tyrosine kinase family;     -   e) compounds targeting, decreasing or inhibiting the activity of         the Axl receptor tyrosine kinase family;     -   f) compounds targeting, decreasing or inhibiting the activity of         the c-Met receptor;     -   g) compounds targeting, decreasing or inhibiting the activity of         the Kit/SCFR receptor tyrosine kinase;     -   h) compounds targeting, decreasing or inhibiting the activity of         the C-kit receptor tyrosine kinases—(part of the PDGFR family),         such as compounds which target, decrease or inhibit the activity         of the c-Kit receptor tyrosine kinase family, especially         compounds which inhibit the c-Kit receptor, e.g., imatinib;     -   i) compounds targeting, decreasing or inhibiting the activity of         members of the c-Abl family and their gene-fusion products,         e.g., BCR-Abl kinase, such as compounds which target decrease or         inhibit the activity of c-Abl family members and their gene         fusion products, e.g., a N-phenyl-2-pyrimidine-amine derivative,         e.g., imatinib, PD180970, AG957, NSC 680410 or PD173955 from         ParkeDavis;     -   j) compounds targeting, decreasing or inhibiting the activity of         members of the protein kinase C(PKC) and Raf family of         serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK         and Ras/MAPK family members, or PI(3) kinase family, or of the         PI(3)-kinase-related kinase family, and/or members of the         cyclin-dependent kinase family (CDK) and are especially those         staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330,         e.g., midostaurin; examples of further compounds include, e.g.,         UCN-01; safingol; BAY 43-9006; Bryostatin 1; Perifosine;         Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;         LY333531/LY379196; isochinoline compounds, such as those         disclosed in WO 00/09495; FTIs; PD184352; or QAN697 (a PI3K         inhibitor);     -   k) compounds targeting, decreasing or inhibiting the activity of         protein-tyrosine kinase inhibitors, such as compounds which         target, decrease or inhibit the activity of protein-tyrosine         kinase inhibitors include imatinib mesylate (GLEEVEC) or         tyrphostin. A tyrphostin is preferably a low molecular weight         (Mr<1500) compound, or a pharmaceutically acceptable salt         thereof, especially a compound selected from the         benzylidenemalonitrile class or the S-arylbenzenemalonirile or         bisubstrate quinoline class of compounds, more especially any         compound selected from the group consisting of Tyrphostin         A23/RG-50810, AG 99, Tyrphostin AG 213, Tyrphostin AG 1748,         Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44 (+)         enantiomer, Tyrphostin AG 555, AG 494, Tyrphostin AG 556, AG957         and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic         acid adamantyl ester, NSC 680410, adaphostin; and     -   l) compounds targeting, decreasing or inhibiting the activity of         the epidermal growth factor family of receptor tyrosine kinases         (EGFR, ErbB2, ErbB3, ErbB4 as homo- or hetero-dimers), such as         compounds which target, decrease or inhibit the activity of the         epidermal growth factor receptor family are especially         compounds, proteins or antibodies which inhibit members of the         EGF receptor tyrosine kinase family, e.g., EGF receptor, ErbB2,         ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are         in particular those compounds, proteins or monoclonal antibodies         generically and specifically disclosed in WO 97/02266, e.g., the         compound of Example 39, or in EP 0 564 409; WO 99/03854; EP         0520722; EP 0 566 226; EP 0 787 722;     -   EP 0 837 063; U.S. Pat. No. 5,747,498; WO 98/10767; WO 97/30034;         WO 97/49688; WO 97/38983 and, especially, WO 96/30347, e.g.,         compound known as CP 358774; WO 96/33980, e.g., compound ZD         1839; and WO 95/03283, e.g., compound ZM105180, e.g.,         trastuzumab (HERCEPTIN), cetuximab, Iressa, Tarceva, OSI-774,         CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11,         E6.3 or E7.6.3; and 7H-pyrrolo-[2,3-d]pyrimidine derivatives         which are disclosed in WO 03/013541.

Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition, e.g., thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, e.g., inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, e.g., okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoic acid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor, as used herein, includes, but is not limited to, e.g., Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g., 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid or lumiracoxib.

The term “bisphosphonates”, as used herein, includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. “Etridonic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark DIDRONEL. “Clodronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark BONEFOS. “Tiludronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark SKELID. “Pamidronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark AREDIA™“Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark FOSAMAX. “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark BONDRANAT. “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark ACTONEL. “Zoledronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOMETA. The term “mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor”, as used herein, refers to compounds which target, decrease or inhibit heparin sulphate degradation. The term includes, but is not limited to, PI-88.

The term “biological response modifier”, as used herein, refers to a lymphokine or interferons, e.g., interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g., H-Ras, K-Ras or N-Ras, as used herein, refers to compounds which target, decrease or inhibit the oncogenic activity of Ras, e.g., a “farnesyl transferase inhibitor”, e.g., L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor”, as used herein, refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g., telomestatin.

The term “methionine aminopeptidase inhibitor”, as used herein, refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are, e.g., bengamide or a derivative thereof.

The term “proteasome inhibitor”, as used herein, refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, e.g., PS-341 and MLN 341.

The term “matrix metalloproteinase inhibitor” or “MMP inhibitor”, as used herein, includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “agents used in the treatment of hematologic malignancies”, as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors, e.g., compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, e.g., compounds which target, decrease or inhibit anaplastic lymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g., PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

The term “HSP90 inhibitors”, as used herein, includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteasome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative, other geldanamycin related compounds, radicicol and HDAC inhibitors.

The term “antiproliferative antibodies”, as used herein, includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erlotinib (Tarceva™), bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibody. By antibodies is meant, e.g., intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g., Patents International, e.g., IMS World Publications.

The above-mentioned compounds, which can be used in combination with a compound of the formula (I), can be prepared and administered as described in the art, such as in the documents cited above.

A compound of the formula (I) may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or especially radiation.

A compound of formula (I) may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

By “combination”, there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect or any combination thereof. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of formula I and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of formula (I) and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

The following examples are merely illustrative and not meant to limit the scope of the present claims in any manner.

EXAMPLES

The following examples serve to illustrate the invention without limiting the scope thereof:

Temperatures are measured in degrees Celsius. Unless otherwise indicated, the reactions take place at rt. The following HPLC/MS and MS methods are used in the preparation of the Intermediates and Examples:

HPLC Method: Method A

HPLC linear gradient between A=H₂O/TFA 1000:1 and B=acetonitrile/TFA 1000:1 Grad 1: 2-100% Bin 4.5 min and 1 min at 100% B; column: Chromolith Performance 100 mm×4.5 mm (Merck, Darmstadt, Germany); flow rate 2 ml/min. Detection at 215 nM.

LC-MS Method: Method B

System: Agilent 1100 Series with Waters Micromass ZQ Column: XBridge C18, 3×30 mm, 2.5 micron Flow Rate: 1.4-2.4 mL/min Eluent A: H₂O, containing 5% acetonitrile and 0.8% HCOOH Eluent B: acetonitrile, containing 0.6% HCOOH

Gradient: 0-2.4 min: 10% to 95% of B

In the following examples, the abbreviations given below are used:

-   -   DCM dichloromethane     -   DIPEA N,N-diisopropylethylamine     -   DMA dimethylacetamide     -   DME 1,2-dimethoxyethane     -   DMF N,N-dimethylformamide     -   DMSO dimethyl sulfoxide     -   EtOAc ethyl acetate     -   h hour(s)     -   HPLC high performance liquid chromatography     -   HV high vacuum     -   Intermed. intermediate     -   iPrMgCl isopropylmagnesium chloride     -   iPrOH isopropanol     -   LC-MS liquid chromatography coupled with mass spectrometry     -   MeOH methanol     -   ml milliliter(s)     -   min minute(s)     -   MS-ES electrospray mass spectrometry     -   NMP N-methyl-2-pyrrolidone     -   PdCl₂(dppf)         [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)     -   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium (II) dichloride     -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (0)     -   Prep.HPLC preparative high performance liquid chromatography     -   qt quintuplet     -   RM reaction mixture     -   rt room temperature     -   TEA triethylamine     -   TFA trifluoroacetic acid     -   THF tedrahydrofurane     -   t_(R) retention time     -   TPTU         O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′-N′-tetramethyluronium         tetrafluoroborate

Intermediate A: 8-Bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

NaOH (0.568 g, 14.19 mmol) and tetrabutylammonium bromide (0.229 g, 0.710 mmol) were added to a mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 3.10 g, 7.100 mmol) in DCM (108 ml) and H₂O (54 ml) and stirred at rt for 5 min. Then iodomethane (1.52 ml, 24.1 mmol) was added and the mixture was stirred for 14 h at rt. Iodomethane (0.4 ml, 6.35 mmol) was added and the RM was stirred at rt for 23.5 h. Then the RM was extracted with DCM (2×), washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and evaporated to dryness. The residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH 0%-4.5%) to give the title compound as a brownish solid (HPLC: t_(R) 2.37 min (Method A); M+H=374 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.08 (s, 1H), 7.91-7.99 (m, 1H), 7.64-7.71 (m, 1H), 7.41-7.47 (m, 1H), 3.90 (s, 3H), 3.55 (s, 3H), 1.94 (s, 3H))

Stage A.1: 8-Bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a solution of 6-bromo-N*4*-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-3,4-diamine (Stage A.2, 3.15 g, 8.15 mmol) and TEA (1.36 ml, 9.79 mmol) in DCM (65 ml) was added under argon, after cooling with an ice-bath, a solution of trichloromethyl chloroformate (1.08 ml, 8.97 mmol in DCM (65 ml). The mixture was stirred for 25 min at 0° C. Then the RM was quenched with sat. aqueous NaHCO₃ (300 ml) and 10 M aquoeus NaOH (4 ml) and well stirred. The phases were separated and extracted with EtOAc (3×). The combined organic layers were washed with brine (2×), dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a brownish solid (HPLC t_(R) 2.29 min (Method A); M+H=360; M−H=358 MS-ES)

Stage A.2 6-Bromo-N*4*-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-3,4-diamine

(6-Bromo-3-nitro-quinolin-4-yl)-(1,3-dimethyl-1H-pyrazol-4-yl)-amine (Stage A.3, 3.67 g 9.73 mmol) was shacked in MeOH/THF 1:1 (120 ml) under 1.1 bar H₂ in presence of Raney nickel (1.50 g) as catalyst for 5 h at rt. The RM was filtered over celite, the catalyst was washed with MeOH/DCM and the solution was evaporated to dryness to give the title compound as a red solid (HPLC t_(R) 2.44 min (Method A); M+H=334; M−H=332 MS-ES)

Stage A.3 (6-Bromo-3-nitro-quinolin-4-yl)-(1,3-dimethyl-1H-pyrazol-4-yl)-amine

To a mixture of 6-bromo-4-chloro-3-nitro-quinoline (Stage A.4, 3.0 g, 20.43 mmol) and 4-amino-1,3-dimethylpyrazole*HCl (ChemCollect, Remscheid, Germany, 1.85 g, 12.53 mmol) in DMA (45 ml) was added 1,2,2,6,6-pentamethylpiperidine (6.67 ml, 36.5 mmol). The RM was stirred at 50° C. for 4.5 h. Then the RM was cooled down to rt and quenched with H₂O. The suspension was filtered, the solid cake was washed with H₂O and dried under vacuum, before being dissolved in EtOAc. The solution was washed with brine (2×), dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as an orange solid (HPLC t_(R) 2.55 min (Method A); M+H=362; M−H=360 MS-ES)

Stage A.4 6-Bromo-4-chloro-3-nitro-quinoline

6-Bromo-3-nitro-quinolin-4-ol (Fluorochem Ltd., Derbyshire, UK, 10 g, 37.2 mmol) was added to POCl₃ (70 ml). The RM was stirred at 120° C. for 17 h. Then the RM was cooled with an ice-bath, before being slowly dropped onto ice-water. The precipitate was filtered and washed with cold water. The residue was dissolved in DCM, washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a beige solid (HPLC t_(R) 3.64 min (Method A))

The following intermediates were synthesized in a similar manner as described for intermediate A using as replacement for the 4-amino-1,3-dimethylpyrazole.HCl a different aminopyrrazole starting material:

-   5-Amino-1-ethylpyrazole (Aldrich, Buchs, Switzerland; B) -   5-Amino-1,3-dimethylpyrazole (Aldrich, Buchs, Switzerland; C) -   5-Amino-1-methyl-3-(trifluoromethyl)pyrazole (Art-Chem, Akos,     Steinen, Germany; D) -   5-Amino-1-methylpyrazole (Combi-Blocks, San Diego, USA; E) -   4-Amino-1-ethyl-3-methylpyrazole.HCl (Art-Chem, Akos, Steinen,     Germany; F) -   4-Amino-1-isopropyl-3-methylpyrazole. HCl (Art-Chem, Akos, Steinen,     Germany; G) -   4-Amino-1,3,5-trimethylpyrazole (ABCR, Karlsruhe, Germany; H) -   5-Amino-1,4-dimethylpyrazole (ChemBridge, San Diego, USA; I) -   4-Amino-1,5-dimethylpyrazole.2HCl (Art-Chem, Akos, Steinen, Germany;     J)

MS-ES HPLC Intermed. structure Name of the intermediate (M + H) t_(R) (min) B

8-Bromo-1-(2-ethyl-2H-pyrazol-3-yl)- 3-methyl-1,3-dihydro-imidazo[4,5- c]quinolin-2-one  372, 374 2.66 C

8-Bromo-1-(2,5-dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  372, 374 2.65 D

8-Bromo-3-methyl-1-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yl)-1,3- dihydro-imidazo[4,5-c]quinolin-2-one  426, 428 3.22 E

8-Bromo-3-methyl-1-(2-methyl-2H- pyrazol-3-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  358, 360 2.54 F

8-Bromo-1-(1-ethyl-3-methyl-1H- pyrazol-4-yl)-3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  386, 388 2.54 G

8-Bromo-1-(1-isopropyl-3-methyl- 1H-pyrazol-4-yl)-3-methyl-1,3- dihydro-imidazo[4,5-c]quinolin-2-one  400, 402 2.70 H

8-Bromo-3-methyl-1-(1,3,5-trimethyl- 1H-pyrazol-4-yl)-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  386, 388 2.44 I

8-Bromo-1-(2,4-dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  372, 374 2.65 J

8-Bromo-1-(1,5-dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  372, 374 2.39 K

8-Bromo-1-(3-chloro-1-methyl-1H- pyrazol-4-yl)-3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  392, 394 BrCl pattern 2.55 L

2-[4-(8-Bromo-3-methyl-2-oxo-2,3- dihydro-imidazo[4,5-c]quinolin-1-yl)- 3-methyl-pyrazol-1-yl]-N,N-dimethyl- acetamide  443, 445 2.39 M

8-Bromo-3-methyl-1-[3-methyl-1-(2- morpholin-4-yl-2-oxo-ethyl)-1H- pyrazol-4-yl]-1,3-dihydro- imidazo[4,5-c]quinolin-2-one  475, 477 2.52 N

8-Bromo-1-[1-(2-methoxy-ethyl)-3,5- dimethyl-1H-pyrazol-4-yl]-3-methyl- 1,3-dihydro-imidazo[4,5-c]quinolin-2- one  430, 432 2.51 O

2-[4-(8-Bromo-3-methyl-2-oxo-2,3- dihydro-imidazo[4,5-c]quinolin-1-yl)- 3,5-dimethyl-pyrazol-1-yl]-N,N- dimethyl-acetamide  457, 459 2.36 P

2-[4-(8-Bromo-3-methyl-2-oxo-2,3- dihydro-imidazo[4,5-c]quinolin-1-yl)- 3-methyl-pyrazol-1-yl]-N-ethyl-N- methyl-acetamide  457, 459 2.46

Stage K.1 3-Chloro-1-methyl-1H-pyrazol-4-ylamine

3-Chloro-1-methyl-4-nitro-1H-pyrazole (Stage K.2, 1.0 g 6.19 mmol) was shacked in MeOH/THF 1:1 (62 ml) under 1.1 bar H₂ in presence of Raney nickel (0.35 g) as catalyst for 24 h at rt. The RM was filtered over Celite, the catalyst was washed several times with MeOH/THF and the filtrate was evaporated to dryness to give the title compound as a blue oil (HPLC t_(R) 0.89 min (Method A); M+H=132 MS-ES)

Stage K.2 3-Chloro-1-methyl-4-nitro-1H-pyrazole

To a solution of 3-chloro-1-methylpyrazole (Maybridge, Basel, Switzerland, 953 mg, 8.18 mmol) in concentrated sulfuric acid (1.4 ml), cooled with an ice-bath, was added over 30 min fuming nitric acid (1.19 mL, 28.6 mmol). The reaction mixture was stirred at rt for 2 h before being poured on ice/water and extracted with EtOAc (2×). The organic layers were washed with saturated aqueous NaHCO₃ (2×) and brine, dried over Na₂SO₄, filtered, evaporated and dried over vacuum to give the title compound as a white solid (HPLC t_(R) 2.24 min (Method A); M+H=162 MS-ES)

Stage L.1 2-(4-Amino-3-methyl-pyrazol-1-yl)-N,N-dimethyl-acetamide

The title compound was synthesized in a similar manner as described for stage K.1 using N,N-dimethyl-2-(3-methyl-4-nitro-pyrazol-1-yl)-acetamide (stage L.2) to give the title compound as an oil (HPLC t_(R) 1.03 min (Method A); M+H=183 MS-ES).

Stage L.2 N,N-Dimethyl-2-(3-methyl-4-nitro-pyrazol-1-yl)-acetamide

To a solution of 3-methyl-4-nitropyrazole (Apollo, Cheshire, UK, 500 mg, 3.93 mmol) in DMF (10 ml) was added 55% NaH in oil (198 mg, 4.54 mmol) and the reaction mixture was stirred for 30 min at rt. Then to the reaction mixture was added a solution of 2-bromo-N,N-dimethylacetamide (stage L.3, 720 mg, 4.34 mmol) in DMF (3 ml). The reaction mixture was stirred for 1 h at rt then quenched with saturated aqueous NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried over Na₂SO₄, filtered and evaporated. The crude product was purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 97:2 to 75:25; riverse phase silica gel). The fractions containing product were collected together, basified with NaHCO₃ and concentrated before being extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a white solid (HPLC t_(R) 2.06 min (Method A); M+H=213 MS-ES).

Stage L.3 2-Bromo-N,N-dimethyl-acetamide

To a solution of bromoacetylbromide (Aldrich, Buchs, Switzerland, 4.56 g, 22.6 mmol) in dichloromethane (90 ml) were added sequentially a 2 M solution of dimethylamine in THF (Aldrich, Buchs, Switzerland, 14 ml, 28 mmol) and triethylamine (3.8 ml, 27.3 mmol). The reaction mixture was stirred for 1 h at rt then diluted with dichloromethane and washed with 2 M aqueous HCl, sat. aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a brownish oil (HPLC t_(R) 1.64 min (Method A); M+H=166, 168 MS-ES).

Stage M.1 2-(4-Amino-3-methyl-pyrazol-1-yl)-1-morpholin-4-yl-ethanone

The title compound was synthesized in a similar manner as described for Stage L.1-2 using 2-bromo-1-morpholin-4-yl-ethanone (ChemBridge, San Diego, USA) to give the title compound as a pink solid (HPLC t_(R) 1.05 min (Method A); M+H=225 MS-ES).

Stage N.1 1-(2-Methoxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-ylamine

The title compound was synthesized in a similar manner as described for Stage K.1 using 1-(2-methoxy-ethyl)-3,5-dimethyl-4-nitro-1H-pyrazole (Stage N.2) to give the title compound as an oil (HPLC t_(R) 1.15 min (Method A); M+H=170 MS-ES).

Stage N.2 1-(2-Methoxy-ethyl)-3,5-dimethyl-4-nitro-1H-pyrazole

To a solution of 3,5-dimethyl-4-nitropyrazole (Fluorochem, Derbyshire, UK, 989 mg, 7.01 mmol) in DMF (40 ml) was added in two portions 55% NaH in oil (420 mg, 9.63 mmol). The reaction mixture was stirred for 30 min at rt then 2-bromoethyl methyl ether (Aldrich, Buchs, Switzerland, 1.17 g, 8.42 mmol) was added and the reaction mixture stirred for 2 h at rt. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water (2×) and brine (2×), dried over Na₂SO₄, filtered and evaporated. The crude product was purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 50:50; riverse phase silica gel). The fractions containing product were collected together, basified with NaHCO₃ and concentrated before being extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a white solid (HPLC t_(R) 2.57 min (Method A); M+H=200 MS-ES)

Stage O.1 2-(4-Amino-3,5-dimethyl-pyrazol-1-yl)-N,N-dimethyl-acetamide

The title compound was synthesized in a similar manner as described for stage L.1-3 using 3,5-dimethyl-4-nitropyrazole (Fluorochem, Derbyshire, UK) to give the title compound as an oil (HPLC t_(R) 1.13 min (Method A); M+H=197 MS-ES).

Stage P.1 2-(4-Amino-3-methyl-pyrazol-1-yl)-N-ethyl-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Stage K1 using 2-bromo-1-morpholin-4-yl-ethanone (ChemBridge, San Diego, USA) to give the title compound as a pink solid (HPLC t_(R) 1.05 min (Method A); M+H=225 MS-ES).

Stage P.2 N-Ethyl-N-methyl-2-(3-methyl-4-nitro-pyrazol-1-yl)-acetamide

A mixture of 3-Methyl-4-nitro-pyrazol-1-yl-acetic acid methylester (ChemCollect, Remscheid, Germany, 1.0 g, 5.02 mmol) in dioxane (40 ml) and 1 M aqueous LiOH (10 ml, 10 mmol) was stirred for 1 h at 50° C. Were added 2 M aqueous HCl (5 ml, 10 mmol) and the solution was evaporated to dryness. The dried residue, TPTU (2.98 g, 10.04 mmol) and DIPEA (2.63 ml, 15.06 mmol) in DMA (30 ml) was stirred under argon at rt for 5 min. Then N-ethylmethylamine (Aldrich, Buchs, Switzerland, 1.78 ml, 20.08 mmol) was added and the RM was stirred at rt for 20 h. The RM was diluted with EtOAc and washed with saturated aqueous NaHCO₃ (2×) and with brine. The aqueous layers were extracted with dichloromethane (3×) and the combined organic layers were dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMA and purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 97:3 to 75:25). The fractions containing products were collected together and concentrated. The solution was basified with NaHCO₃ and extracted with dichloromethane (2×), The organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a light yellow oil. (HPLC: t_(R) 2.25 min (Method A); M+H=227, M−H=225 MS-ES)

Intermediate Q: 8-Bromo-1-(3,5-dimethyl-isoxazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The intermediate Q was synthesized in a similar manner as described for intermediate A and stage A1 to A3 using as replacement for the (6-bromo-3-nitro-quinolin-4-yl)-(1,3-dimethyl-1H-pyrazol-4-yl)-amine the (6-bromo-3-nitro-quinolin-4-yl)-(3,5-dimethyl-isoxazol-4-yl)-amine (stage Q1). (HPLC: t_(R) 2.58 min (Method A); M+H=373, 375 MS-ES)

Stage Q1: (6-Bromo-3-nitro-quinolin-4-yl)-(3,5-dimethyl-isoxazol-4-yl)-amine

A mixture of 6-bromo-4-chloro-3-nitro-quinoline (Stage A.4, 1.1 g, 3.83 mmol) and 3,5-dimethyl-4-aminoisoxazol (Aldrich, Buchs, Switzerland, 472 mg, 4.21 mmol) in acetic acid (10 ml) was stirred at rt for 4. h. Then the RM was quenched with H₂O (40 ml). The suspension was filtered, the solid cake was washed with H₂O (2×) and dried under vacuum, before being dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as an orange solid (HPLC t_(R) 2.96 min (Method A); M+H=363, 365; M−H=361, 363 MS-ES).

Example 1.1 8-(3,4-Dimethoxy-phenyl)-1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of 8-bromo-1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate J, 50 mg, 0.132 mmol), 3,4-dimethoxyphenylboronic acid (Aldrich, Buchs, Switzerland, 29 mg, 0.156 mmol) and PdCl₂(PPh₃)₂ (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K₂CO₃ (0.329 ml) was stirred under argon at 105° C. for 1.5 h. Then the RM was cooled to rt, diluted with MeOH/DMA+3 drops TFA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 55:45). The fractions containing product were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as an off-white solid. (HPLC: t_(R) 2.66 min (Method A); M+H=430 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.08-8.01 (m, 1H), 7.95-7.88 (m, 1H), 7.76 (s, 1H), 7.60-7.55 (m, 1H), 7.13-7.08 (m, 1H), 7.05-7.00 (m, 1H), 6.99-6.94 (m, 1H), 3.88-382 (m, 6H), 3.78 (s, 3H), 3.56 (s, 3H), 2.11 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using as replacement for intermediate J a different intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 1.2  B

8-(3,4-Dimethoxy- phenyl)-1-(2-ethyl- 2H-pyrazol-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 430 2.76 1.3  E

8-(3,4-Dimethoxy- phenyl)-3-methyl-1- (2-methyl-2H- pyrazol-3-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 416 2.68 1.4  C

8-(3,4-Dimethoxy- phenyl)-1-(2,5- dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 430 2.79 1.5  G

8-(3,4-Dimethoxy- phenyl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 458 2.82 1.6  F

8-(3,4-Dimethoxy- phenyl)-1-(1-ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 444 2.72 1.7  I

8-(3,4-Dimethoxy- phenyl)-1-(2,4- dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 430 2.77 1.8  A

8-(3,4-Dimethoxy- phenyl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 430 2.65 1.9  H

8-(3,4-Dimethoxy- phenyl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 444 2.69 1.10 K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-(3,4-dimethoxy- phenyl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 450 2.73

Example 2.1 1-(2,4-Dimethyl-2H-pyrazol-3-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,4-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate I, 40 mg, 0.106 mmol) and 2-methoxy-5-pyridineboronic acid (Aldrich, Buchs, Switzerland, 20 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.69 min (Method A); M+H=401 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.03 (s, 1H), 8.27-8.21 (m, 1H), 8.16-8.09 (m, 1H), 7.96-7.89 (m, 1H), 7.84-7.77 (m, 1H), 7.65 (s, 1H), 7.00-6.88 (m, 2H), 3.88 (s, 3H), 3.61 (s, 6H), 1.82 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-methoxy-5-pyridineboronic acid and the specified intermediate.

MS-ES HPLC Example Intermed. structure Name of the example (M + H) t_(R) (min) 2.2 E

8-(6-Methoxy-pyridin- 3-yl)-3-methyl-1-(2- methyl-2H-pyrazol-3- yl)-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 387 2.60 2.3 C

1-(2,5-Dimethyl-2H- pyrazol-3-yl)-8-(6- methoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 401 2.72 2.4 H

8-(6-Methoxy-pyridin- 3-yl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 415 2.61 2.5 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-(6- methoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 401 2.55 2.6 B

1-(2-Ethyl-2H-pyrazol- 3-yl)-8-(6-methoxy- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 401 2.69 2.7 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-8-(6- methoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 415 2.66 2.8 G

1-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-8-(6-methoxy- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 429 2.78 2.9 J

1-(1,5-Dimethyl-1H- pyrazol-4-yl)-8-(6- methoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 401 2.56

Example 3.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 60 mg, 0.161 mmol) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany, 36 mg, 0.211 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.69 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.24 (m, 1H), 8.15-8.05 (m, 2H), 7.92-7.85 (m, 1H), 7.79-7.72 (m, 1H), 7.47 (s, 1H), 6.94-6.87 (m, 1H), 4.32 (q, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.32 (t, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 6-ethoxypyridine-3-boronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 3.2  D

8-(6-Ethoxy-pyridin- 3-yl)-3-methyl-1-(2- methyl-5- trifluoromethyl-2H- pyrazol-3-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 469 3.31 3.3  H

8-(6-Ethoxy-pyridin- 3-yl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 429 2.73 3.4  B

8-(6-Ethoxy-pyridin- 3-yl)-1-(2-ethyl-2H- pyrazol-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 415 2.58 3.5  F

8-(6-Ethoxy-pyridin- 3-yl)-1-(1-ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 429 2.80 3.6  J

1-(1,5-Dimethyl-1H- pyrazol-4-yl)-8-(6- ethoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 415 2.68 3.7  G

8-(6-Ethoxy-pyridin- 3-yl)-1-(1-isopropyl- 3-methyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 443 2.94 3.8  K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-(6-ethoxy- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 435 2.81 3.9  L

2-{4-[8-(6-Ethoxy- pyridin-3-yl)-3- methyl-2-oxo-2,3- dihydro-imidazo[4,5- c]quinolin-1-yl]-3- methyl-pyrazol-1-yl}- N,N-dimethyl- acetamide 486 2.68 3.10 M

8-(6-Ethoxy-pyridin- 3-yl)-3-methyl-1-[3- methyl-1-(2- morpholin-4-yl-2- oxo-ethyl)-1H- pyrazol-4-yl]-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 528 2.66 3.11 N

8-(6-Ethoxy-pyridin- 3-yl)-1-[1-(2- methoxy-ethyl)-3,5- dimethyl-1H-pyrazol- 4-yl]-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 473 2.76 3.12 O

2-{4-[8-(6-Ethoxy- pyridin-3-yl)-3- methyl-2-oxo-2,3- dihydro-imidazo[4,5- c]quinolin-1-yl]-3,5- dimethyl-pyrazol-1- yl}-N,N-dimethyl- acetamide 500 2.62

Example 4.1 8-(6-Dimethylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 50 mg, 0.125 mmol) and 2-(dimethylamino)pyridine-5-boronic acid hydrate (Fluorochem Ltd., Derbyshire, United Kingdom, 31 mg, 0.163 mmol) to give the title compound as a yellow solid. (HPLC: t_(R) 2.31 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.27-8.18 (m, 2H), 8.07-7.99 (m, 1H), 7.90-7.82 (m, 1H), 7.62-7.55 (m, 1H), 7.41 (s, 1H), 6.70-6.61 (m, 1H), 4.62-4.49 (m, 1H), 3.56 (s, 3H), 3.04 (s, 6H), 1.96 (s, 3H), 1.49 (s, 6H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-(dimethylamino)pyridine-5-boronic acid hydrate and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 4.2 F

8-(6-Dimethylamino- pyridin-3-yl)-1-(1- ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 428 2.25 4.3 H

8-(6-Dimethylamino- pyridin-3-yl)-3- methyl-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 428 2.25 4.4 J

8-(6-Dimethylamino- pyridin-3-yl)-1-(1,5- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 414 2.21 4.5 A

8-(6-Dimethylamino- pyridin-3-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 414 2.19 4.6 C

8-(6-Dimethylamino- pyridin-3-yl)-1-(2,5- dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 414 2.31 4.7 E

8-(6-Dimethylamino- pyridin-3-yl)-3- methyl-1-(2-methyl- 2H-pyrazol-3-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 400 2.23 4.8 B

8-(6-Dimethylamino- pyridin-3-yl)-1-(2- ethyl-2H-pyrazol-3- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 414 2.28 4.9 K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-(6- dimethylamino- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 434 2.24

Example 5.1 8-(6-Azetidin-1-yl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-azetidin-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 5.1.1, 39 mg, 0.150 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.24 min (Method A); M+H=426 MS-ES; ¹H-NMR (de-DMSO, 400 MHz) 8.91 (s, 1H), 8.25-8.18 (m, 1H), 8.14-8.09 (m, 1H), 8.06-8.02 (m, 1H), 7.89-7.81 (m, 1H), 7.62-7.53 (m, 1H), 7.42 (s, 1H), 6.48-6.42 (m, 1H), 4.01-3.93 (m, 4H), 3.91 (s, 3H), 3.56 (s, 3H), 2.36-2.28 (m, 2H), 1.96 (s, 3H))

Stage 5.1.1 2-Azetidin-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

A mixture of 2-azetidin-1-yl-5-bromo-pyridine (Stage 5.1.2, 55 mg, 0.259 mmol), bis(pinacolato)-diborane (74 mg, 0.285 mmol), potassium acetate (76 mg, 0.778 mmol) and PdCl₂(dppf) (9 mg, 0.012 mmol) in dioxane (1.2 ml) was stirred in a closed vial flushed with argon at 90° C. for 2 h. Then the RM was diluted with EtOAc and washed with brine (2×). The organic layer was dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a crude brownish sticky solid. (HPLC: t_(R) 1.79 min (Method A); M+H=261 MS-ES).

Stage 5.1.2 2-Azetidin-1-yl-5-bromo-pyridine

A mixture of 5-bromo-2-chloropyridine (Sigma-Aldrich, Buchs, Switzerland, 196 mg, 1.018 mmol), azetidine (Sigma-Aldrich, Buchs, Switzerland, 0.213 ml, 3.06 mmol) and pyridine (0.124 ml, 1.528 mmol) in DMA (2.5 ml) was heated under microwave irradiation at 150° C. for 10 min and 170° C. for 10 min. The reaction was not completed. Again azetidine (0.106 ml) was added and the RM was heated under microwave irradiation at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO₃ (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as an off-white solid. (HPLC: t_(R) 1.97 min (Method A); M+H=213, 215 (Br-pattern) MS-ES. ¹H-NMR (d₆-DMSO, 400 MHz) 8.12 (s, 1H), 7.70-7.60 (m, 1H), 6.37-6.29 (m, 1H), 3.96-3.86 (m, 4H), 2.34-2.24 (m, 2H))

The following example was synthesized in a similar manner as described for Example 1.1 using 2-azetidin-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 5.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 5.2 G

8-(6-Azetidin-1-yl- pyridin-3-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 454 2.35

Example 6.1 8-(2-Dimethylamino-pyrimidin-5-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 50 mg, 0.125 mmol) and 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 38 mg, 0.153 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.68 min (Method A); M+H=443 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.46 (s, 2H), 8.20 (s, 1H), 8.09-8.02 (m, 1H), 7.91-7.84 (m, 1H), 7.38 (s, 1H), 4.60-4.51 (m, 1H), 3.56 (s, 3H), 3.13 (s, 6H), 1.97 (s, 3H), 1.49-1.44 (m, 6H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 6.2 A

8-(2-Dimethylamino- pyrimidin-5-yl)-1- (1,3-dimethyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 415 2.46 6.3 K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-(2- dimethylamino- pyrimidin-5-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 435 2.56 6.4 F

8-(2-Dimethylamino- pyrimidin-5-yl)-1-(1- ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 429 2.48

Example 7.1 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-methyl-8-(6-methyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate C, 50 mg, 0.135 mmol) and 2-methylpyridine-5-boronic acid (Frontier Scientific, Logan, USA, 28 mg, 0.181 mmol) to give the title compound as a red solid. (HPLC: t_(R) 2.20 min (Method A); M+H=385 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.02 (s, 1H), 8.62-8.52 (m, 1H), 8.17-8.08 (m, 1H), 8.00-7.91 (m, 1H), 7.81-7.73 (m, 1H), 7.39-7.32 (m, 1H), 7.13 (s, 1H), 6.52 (s, 1H), 3.62 (s, 3H), 3.51 (s, 3H), 2.55-2.45 (3H), 2.29 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 2-methylpyridine-5-boronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 7.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-3- methyl-8-(6-methyl- pyridin-3-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2- one 385 2.05

Example 8.1 3-Methyl-1-(2-methyl-2H-pyrazol-3-yl)-8-(6-trifluoromethyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 58 mg, 0.163 mmol) and 2-trifluoromethylpyridine-5-boronic acid (Frontier Scientific, Logan, USA, 40.5 mg, 0.212 mmol) to give the title compound as a red solid. (HPLC: t_(R) 2.87 min (Method A); M+H=425 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.08 (s, 1H), 8.82 (d, 1H), 8.27-8.16 (m, 2H), 8.10-7.98 (m, 2H), 7.82 (d, 1H), 7.18-7.16 (m, 1H), 6.72 (s, 1H), 3.72 (s, 3H), 3.63 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 2-trifluoromethylpyridine-5-boronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 8.2 C

1-(2,5-Dimethyl-2H- pyrazol-3-yl)-3- methyl-8-(6- trifluoromethyl-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5-c] quinolin-2-one 439 2.94

Example 9 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-8-(2-fluoro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate C, 50 mg, 0.135 mmol) and 2-fluoropyridine-3-boronic acid (Aldrich, Buchs, Switzerland, 25 mg, 0.179 mmol) to give the title compound as a red solid. (HPLC: t_(R) 2.57 min (Method A); M+H=389 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.07 (s, 1H), 8.27-8.22 (m, 1H), 8.18-8.13 (m, 1H), 8.06-7.99 (m, 1H), 7.89-7.83 (m, 1H), 7.51-7.45 (m, 1H), 7.24-7.20 (m, 1H), 6.45 (s, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 2.24 (s, 3H))

Example 10.1 3-Methyl-8-pyridin-3-yl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 39 mg, 0.100 mmol) and 3-pyridineboronic acid (Aldrich, Buchs, Switzerland, 15 mg, 0.122 mmol) to give the title compound as an off-white foam. (HPLC: t_(R) 2.08 min (Method A); M+H=385 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.70-8.64 (m, 1H), 8.60-8.55 (m, 1H), 8.16-8.10 (m, 1H), 7.99-7.92 (m, 1H), 7.90-7.84 (m, 1H), 7.54-7.47 (m, 2H), 3.82 (s, 3H), 3.60 (s, 3H), 2.09 (s, 3H), 1.92 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 3-pyridineboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 10.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-3- methyl-8-pyridin-3-yl- 1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 371 2.01

Example 11 8-(2-Fluoro-pyridin-4-yl)-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 65 mg, 0.181 mmol) and 2-fluoropyridine-4-boronic acid (Frontier Scientific, Logan, USA, 33 mg, 0.236 mmol) to give the title compound as a pink solid. (HPLC: t_(R) 2.55 min (Method A); M+H=375 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.08 (s, 1H), 8.35-8.26 (m, 1H), 8.22-8.13 (m, 1H), 8.10-8.01 (m, 1H), 7.84-7.76 (m, 1H), 7.43-7.35 (m, 1H), 7.29-7.23 (m, 1H), 7.23-7.16 (m, 1H), 6.73 (s, 1H), 3.68 (s, 3H), 3.60 (s, 3H))

Example 12 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 3-methoxypyridine-5-boronic acid pinacol ester (Aldrich, Buchs, Switzerland, 30 mg, 0.125 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.17 min (Method A); M+H=401 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.39-8.26 (m, 2H), 8.21-8.07 (m, 2H), 8.04-7.96 (m, 1H), 7.66-7.56 (m, 1H), 7.45-7.36 (m, 1H), 3.91 (s, 6H), 3.60 (s, 3H), 1.97 (s, 3H))

Example 13 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-fluoro-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 3-fluoro-2-methoxypyridine-5-boronic acid (Apollo Scientific, Cheshire, United Kingdom, 21 mg, 0.123 mmol) to give the title compound as a pink solid. (HPLC: t_(R) 2.70 min (Method A); M+H=419 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.18-8.05 (m, 3H), 7.96-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.49 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.59 (s, 3H), 1.98 (s, 3H))

Example 14 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid amide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid amide (Stage 14.1.1, 106 mg, 0.427 mmol) to give the title compound as a lightly yellow solid. (HPLC: t_(R) 2.28 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.73-8.67 (m, 1H), 8.22-8.04 (m, 5H), 8.03-7.98 (m, 1H), 7.71-7.61 (m, 2H), 3.92 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))

Stage 14.1.1 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid amide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-pyridine-2-carboxylic acid amide (Combi-Blocks, San Diego, USA, 360 mg, 1.791 mmol) to give the title compound as a brownish sticky solid. (HPLC: t_(R) 2.27 min (Method A); M+H=249 MS-ES.

Example 15.1 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid methylamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methylamide (Stage 15.1.1, 42 mg, 0.160 mmol) to give the title compound as a lightly yellow solid. (HPLC: t_(R) 2.39 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.87-8.80 (m, 1H), 8.71-8.67 (m, 1H), 8.18-8.07 (m, 4H), 8.04-7.98 (m, 1H), 7.65 (s, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 2.83 (s, 3H), 1.97 (s, 3H))

Stage 15.1.1 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methylamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-pyridine-2-carboxylic acid methylamide (Combi-Blocks, San Diego, USA, 240 mg, 1.116 mmol) to give the title compound as a brownish sticky solid. (HPLC: t_(R) 2.46 min (Method A); M+H=263 MS-ES.

The following examples were synthesized in a similar manner as described for Example 1.1 using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methylamide and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 15.2 H

5-[3-Methyl-2-oxo-1- (1,3,5-trimethyl- 1H-pyrazo1-4-yl)- 2,3-dihydro-1H- imidazo[4,5- c]quinolin-8-yl]- pyridine- 2-carboxylic acid methylamide 442 2.45 15.3 G

5-[1-(1-Isopropyl-3- methyl-1H-pyrazol- 4-yl)-3-methyl-2- oxo-2,3-dihydro- 1H-imidazo[4,5- c]quinolin-8-yl]- pyridine-2-carboxylic acid methylamide 456 2.56

Example 16.1 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 80 mg, 0.207 mmol) and 6-(hydroxymethyl)pyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 39 mg, 0.254 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.04 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.61-8.56 (m, 1H), 8.21-8.17 (m, 1H), 8.15-8.09 (m, 1H), 7.97-7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.57-7.49 (m, 2H), 5.47 (t, 1H), 4.61-4.55 (m, 2H), 4.23-4.14 (m, 2H), 3.57 (s, 3H), 1.95 (s, 3H), 1.43 (t, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 6-(hydroxymethyl)pyridine-3-boronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 16.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8- (6-hydroxymethyl- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5-c] quinolin-2-one 401 1.99 16.3 G

8-(6-Hydroxymethyl- pyridin-3-yl)-1- (1-isopropyl-3-methyl- 1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5-c] quinolin-2-one 429 2.11 16.4 H

8-(6-Hydroxymethyl- pyridin-3-yl)-3- methyl-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-1,3-dihydro- imidazo[4,5-c] quinolin-2-one 415 2.04 16.5 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(6- hydroxymethyl- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 421 2.06

Example 17.1 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(2-methoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 49 mg, 0.126 mmol) and 2-methoxy-5-pyrimidineboronic acid (ABCR, Karlsruhe, Germany, 25 mg, 0.162 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.47 min (Method A); M+H=416 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.76-8.68 (m, 2H), 8.23-8.16 (m, 1H), 8.16-8.09 (m, 1H), 7.99-7.93 (m, 1H), 7.52-7.45 (m, 1H), 4.19 (q, 2H), 3.96 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.42 (t, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-methoxy-5-pyrimidineboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 17.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8- (2-methoxy-pyrimidin- 5-yl)-3-methyl- 1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 402 2.38 17.3 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(2- methoxy-pyrimidin-5- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 422 2.49

Example 18 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 18.1.1, 38 mg, 0.137 mmol) to give the title compound as an off-white foam. (HPLC: t_(R) 2.58 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.25 (m, 1H), 8.16-8.04 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.45 (m, 1H), 6.99-6.92 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.64 (m, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.96 (s, 3H))

Stage 18.1.1 2-(2-Methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-(2-methoxy-ethoxy)-pyridine (Stage 18.1.2, 251 mg, 1.082 mmol) to give the title compound as a brownish oil. (HPLC: t_(R) 1.88 min (Method A); M+H=280 MS-ES)

Stage 18.1.2 5-Bromo-2-(2-methoxy-ethoxy)-pyridine

A mixture of NaH 55% (133 mg, 3.06 mmol) in DME (3 ml) was cooled to 0° C., then 2-methoxyethanol (Aldrich, Buchs, Switzerland, 0.362 ml, 4.58 mmol) was added. The solution was stirred at rt for 15 min. After that 5-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 294 mg, 1.528 mmol) was added and the RM was heated by microwaves at 150° C. for 10 min. Then the RM was quenched with saturated aqueous NaHCO₃ (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were evaporated together to give the title compound as a colorless oil. (LC-MS: t_(R) 1.20 min (Method B); M+H=232, 234 (Br-pattern) MS-ES. ¹H-NMR (d₆-DMSO, 400 MHz) 8.28.8.21 (m, 1H), 7.91-7.84 (m, 1H), 6.86-6.79 (m, 1H), 4.31 (t, 2H), 3.62 (t, 2H), 3.26 (s, 3H))

Example 19 8-[6-(2-Benzyloxy-ethoxy)-pyridin-3-yl]-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 50 mg, 0.132 mmol) and 2-(2-benzyloxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 19.1.1, 65 mg, 0.184 mmol) to give the title compound as a white solid. (HPLC: t_(R) 3.12 min (Method A); M+H=521 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.33-8.24 (m, 1H), 8.16-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.75 (m, 1H), 7.51-7.45 (m, 1H), 7.40-7.22 (m, 5H), 7.01-6.93 (m, 1H), 4.55 (s, 2H), 4.47 (t, 2H), 3.92 (s, 3H), 3.78 (t, 2H), 3.57 (s, 3H), 1.97 (s, 3H))

Stage 19.1.1 2-(2-Benzyloxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stages 18.1.1 and 18.1.2 using 2-benzyloxyethanol (Aldrich, Buchs, Switzerland) to give the title compound as a brownish oil. (HPLC: t_(R) 2.59 min (Method A); M+H=356 MS-ES)

Example 20 8-[6-(3-Benzyloxy-propoxy)-pyridin-3-yl]-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 50 mg, 0.132 mmol) and 2-(3-benzyloxy-propoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 20.1.1, 68 mg, 0.184 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 3.22 min (Method A); M+H=535 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.31-8.26 (m, 1H), 8.15-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.45 (m, 1H), 7.35-7.22 (m, 5H), 6.93-6.87 (m, 1H), 4.55 (s, 2H), 4.36 (t, 2H), 3.91 (s, 3H), 3.60-3.55 (m, 5H), 2.05-1.97 (m, 2H), 1.95 (s, 3H))

Stage 20.1.1 2-(3-Benzyloxy-propoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stages 18.1.1 and 18.1.2 using 3-benzyloxypropanol (Aldrich, Buchs, Switzerland) to give the title compound as a brownish oil. (HPLC: t_(R) 2.66 min (Method A); M+H=370 MS-ES)

Example 21.1 8-[6-(2-Hydroxy-ethylamino)-pyridin-3-yl]-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 65 mg, 0.181 mmol) and 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamino]-ethanol (stage 21.1.1, 82 mg, 0.218 mmol) to give the title compound as an off-white foam. (HPLC: t_(R) 2.08 min (Method A); M+H=416 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.12-8.02 (m, 2H), 7.80-7.75 (m, 2H), 7.51-7.44 (m, 1H), 6.95-6.89 (m, 1H), 6.85-6.73 (br, 1H), 6.69 (s, 1H), 6.60-6.53 (m, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 3.54-3.49 (m, 2H), 3.37-3.31 (m, 2H))

Stage 21.1.1 2-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamino]-ethanol

The title compound was synthesized in a similar manner as described for Stages 5.1.1 using 2-(5-Bromo-pyridin-2-ylamino)-ethanol (stage 21.1.2) to give the title compound as a white solid trifluoroacetate salt. (M+H=379 MS-ES)

Stage 21.1.2 2-(5-Bromo-pyridin-2-ylamino)-ethanol

A mixture of 5-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 1 g, 5.2 mmol) and 2-hydroxyethylamine (1.59 g, 26 mmol) in 3 ml DMA was heated by microwaves at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO₃ (50 ml) and extracted with EtOAc. The organic layers were washed with saturated aqueous NaHCO₃ (4×), dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (DCM/MeOH 0 to 5%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: t_(R) 1.66 min (Method A); M+H=217, 219 (Br-pattern) MS-ES)

The following example was synthesized in a similar manner as described for Example 1.1 using 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamino]-ethanol and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 21.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8- [6-(2-hydroxy- ethylamino)-pyridin-3- yl]-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 430 2.04

Example 22 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methanesulfonyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(methylsulfonyl)pyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 25 mg, 0.125 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.30 min (Method A); M+H=449 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.09-9.01 (m, 3H), 8.32-8.27 (m, 1H), 8.21-8.14 (m, 2H), 8.11-8.06 (m, 1H), 7.67-7.62 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.40 (s, 3H), 1.94 (s, 3H))

Example 23.1 8-(6-Amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-aminopyridine-5-boronic acid pinacol ester (Aldrich, Buchs, Switzerland, 26 mg, 0.125 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.02 min (Method A); M+H=386 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.16-8.10 (m, 1H), 8.07-7.98 (m, 2H), 7.86-7.78 (m, 1H), 7.54-7.46 (m, 1H), 7.42-7.36 (m, 1H), 6.54-6.46 (m, 1H), 6.20 (s, br, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 1.95 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 2-aminopyridine-5-boronic acid pinacol ester and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 23.2 G

8-(6-Amino-pyridin-3- yl)-1-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 414 2.10

Example 24 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-methylpyridine-3-boronic acid (Combi-Blocks, San Diego, USA, 17 mg, 0.123 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.07 min (Method A); M+H=385 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.54-8.48 (m, 1H), 8.45-8.39 (m, 1H), 8.19-8.08 (m, 2H), 7.99-7.92 (m, 1H), 7.71-7.66 (m, 1H), 7.58-7.53 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 2.37 (s, 3H), 1.95 (s, 3H))

Example 25.1 8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-amino-3-(trifluoromethyl)pyridine-5-boronic acid pinacol ester (stage 25.1.1, 37 mg, 0.128 mmol) to give the title compound as a pinkish solid. (HPLC: t_(R) 2.40 min (Method A); M+H=454 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.43-8.36 (m, 1H), 8.16-8.11 (m, 1H), 8.09-8.02 (m, 1H), 7.97-7.90 (m, 1H), 7.76-7.70 (m, 1H), 7.45-7.39 (m, 1H), 6.76 (s, br, 2H), 3.88 (s, 3H), 3.56 (s, 3H), 1.95 (s, 3H))

Stage 25.1.1 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine

The title compound was synthesized in a similar manner as described for stage 5.1.1 using 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (Stage 25.1.2, 8.04 g, 31.7 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 1.62 min (Method A); M+H=289 MS-ES)

Stage 25.1.2 5-Bromo-3-trifluoromethyl-pyridin-2-ylamine

To a solution of 3-trifluoromethyl-pyridin-2-ylamine (Fluorochem Ltd., Derbyshire, United Kingdom, 5.37 g, 32.8 mmol) in 100 ml of dry CH₃CN under argon were added N-bromosuccinimide (6.45 g, 36.2 mmol) in 4 equal portions over a period of 1 h at 0-5° C. The cooling bath was removed and stirring was continued for 3 h. The solvent was evaporated under vacuum, then the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄ and evaporated to give the title compound as a orange oil. (M+H=239; 241).

The following example was synthesized in a similar manner as described for Example 1.1 using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 25.2 O

2-{4-[8-(6-Amino-5- trifluoromethyl- pyridin-3-yl)-3- methyl-2-oxo-2,3- dihydro-imidazo[4,5- c]quinolin-1-yl]-3,5- dimethyl-pyrazol-1- yl}-N,N-dimethyl- acetamide 539 2.34 25.3 H

8-(6-Amino-5- trifluoromethyl- pyridin-3-yl)-3- methyl-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 468 2.39 25.4 G

8-(6-Amino-5- trifluoromethyl- pyridin-3-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 482 2.55 25.5 Q

8-(6-Amino-5- trifluoromethyl- pyridin-3-yl)-1-(3,5- dimethyl-isoxazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 455 2.52 25.6 C

8-(6-Amino-5- trifluoromethyl- pyridin-3-yl)-1-(2,5- dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 454 2.54

Example 26 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyrimidin-5-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and pyrimidine-5-boronic acid (Frontier Scientific, Logan, USA, 16 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.24 min (Method A); M+H=372 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.20 (s, 1H), 9.02 (s, 1H), 8.93 (s, 2H), 8.20-8.12 (m, 2H), 8.06-7.99 (m, 1H), 7.62-7.56 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Example 27.1 8-(3,4-Diethoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 49 mg, 0.126 mmol) and 2-(3,4-diethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (stage 27.1.1, 47 mg, 0.161 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 3.02 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.18 (s, 1H), 8.08-8.02 (m, 1H), 7.95-7.84 (m, 1H), 7.52-7.48 (m, 1H), 7.06-6.97 (m, 3H), 4.22-3.98 (m, 6H), 3.58 (s, 3H), 1.97 (s, 3H) 1.45-1.25 (m, 9H))

Stage 27.1.1 2-(3,4-Diethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 4-Bromo-1,2-diethoxy-benzene (Stage 27.1.2, 500 mg, 2.04 mmol) to give the title compound as a colourless oil. (HPLC: t_(R) 3.94 min (Method A); M+H=293 MS-ES).

Stage 27.1.2 4-Bromo-1,2-diethoxy-benzene

A mixture of 4-bromocatechol (Aldrich, Buchs, Switzerland, 500 mg, 2.65 mmol), potassium carbonate (1.1 g, 7.94 mmol) and iodoethane (1.03 g, 6.61 mmol) in 10 ml DMF was stirred protected from the light for 17 h at rt. The reaction mixture was quenched with 50 ml saturated aqueous NaHCO₃ and extracted with EtOAc (2×). The organic layers were washed with saturated aqueous NaHCO₃ (4×) and brine, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (petrol ether/diethyl ether 0% to 10%) to give the title compound as a colorless oil. (HPLC: t_(R) 3.79 min (Method A)).

The following example was synthesized in a similar manner as described for Example 1.1 using 2-(3,4-diethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 27.2 H

8-(3,4-Diethoxy- phenyl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 472 2.97

Example 28.1 8-(3-Ethoxy-4-methoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 39 mg, 0.100 mmol) and 3-ethoxy-4-methoxyphenylboronic acid (Combi-Blocks, San Diego, USA, 25.5 mg, 0.130 mmol) to give the title compound as an off-white foam. (HPLC: t_(R) 2.86 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.16 (s, 1H), 8.08-8.01 (m, 1H), 7.93-7.87 (m, 1H), 7.52-7.46 (m, 1H), 7.06-6.96 (m, 3H), 4.20-4.03 (m, 4H), 3.77 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.45-1.33 (m, 6H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-ethoxy-4-methoxyphenylboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 28.2 H

8-(3-Ethoxy-4- methoxy-phenyl)-3- methyl-1-(1,3,5- trimethyl-1H-pyrazol-4- yl)-1,3-dihydro- imidazo[4,5-c] quinolin-2-one 458 2.81 28.3 A

1-(1,3-Dimethyl-1H- pyrazo1-4-yl)-8- (3-ethoxy-4-methoxy- phenyl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 444 2.76

Example 29.1 8-(4-Ethoxy-3-methoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 39 mg, 0.100 mmol) and 2-(4-ethoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Stage 29.1.1, 34 mg, 0.123 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.88 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.16 (s, 1H), 8.07-8.02 (m, 1H), 7.94-7.88 (m, 1H), 7.51-7.47 (m, 1H), 7.06-6.96 (m, 3H), 4.20-4.12 (m, 2H), 4.06-3.98 (m, 2H), 3.85 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.42-1.29 (m, 6H))

Stage 29.1.1 2-(4-Ethoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

To a mixture of 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, Buchs, Switzerland, 200 mg, 0.800 mmol), triphenylphosphine (315 mg, 1.200 mmol) and ethanol (0.056 ml, 0.960 mmol) in THF (4 ml) under Argon was added dropwise diisopropyl azodicarboxylate (0.253 ml, 1.20 mmol). The RM was stirred at rt for 17.5 h. Then the RM was diluted with EtOAc and the organic layer was washed with brine (2×), before being dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were together evaporated to give the title compound as a white solid. (HPLC: t_(R) 3.58 min (Method A); M+H=279 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-(4-ethoxy-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 29.2 H

8-(4-Ethoxy-3- methoxy-phenyl)-3- methyl-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-1,3-dihydro- midazo[4,5-c]quinolin- 2-one 458 2.85 29.3 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8- (4-ethoxy-3-methoxy- phenyl)-3-methyl- 1,3-dihydro- imidazo[4,5-c] quinolin-2-one 444 2.80

Example 30.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 2-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Stage 30.1.1, 39 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.71 min (Method A); M+H=474 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.15-8.02 (m, 2H), 7.97-7.89 (m, 1H), 7.59-7.51 (m, 1H), 7.11-7.02 (m, 2H), 7.00-6.94 (m, 1H), 4.16-4.07 (m, 2H), 3.94-3.84 (m, 6H), 3.70-3.64 (m, 2H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H))

Stage 30.1.1 2-[3-Methoxy-4-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

The title compound was synthesized in a similar manner as described for stage 29.1.1 using 2-methoxyethanol (Aldrich, Buchs, Switzerland) to give the title compound as a colorless oil. (HPLC: t_(R) 3.42 min (Method A); M+H=309 MS-ES)

The following example was synthesized in a similar manner as described for Example 1.1 using 2-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 30.2 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)- 8-[3-methoxy-4-(2- methoxy-ethoxy)- phenyl]-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 488 2.78

Example 31 8-(4-Hydroxy-3-methoxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 39 mg, 0.100 mmol) and 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, Buchs, Switzerland, 30 mg, 0.120 mmol) to give the title compound as a lightly yellow foam. (HPLC: t_(R) 2.50 min (Method A); M+H=430 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.23 (s, 1H), 8.93 (s, 1H), 8.06-7.99 (m, 1H), 7.92-7.85 (m, 1H), 7.51-7.46 (m, 1H), 7.03-6.96 (m, 1H), 6.94-6.89 (m, 1H), 6.87-6.81 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.94 (s, 3H))

Example 32.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-hydroxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 3-hydroxyphenylboronic acid (Aldrich, Buchs, Switzerland, 17 mg, 0.123 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.46 min (Method A); M+H=386 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.58 (s, 1H), 8.95 (s, 1H), 8.20-8.11 (m, 1H), 8.10-8.01 (m, 1H), 7.88-7.77 (m, 1H), 7.57-7.47 (m, 1H), 7.31-7.20 (m, 1H), 6.93-6.83 (m, 2H), 6.82-6.73 (m, 1H), 3.95 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 3-hydroxyphenylboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 32.2 H

8-(3-Hydroxy-phenyl)- 3-methyl-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 400 2.52

Example 33 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-fluoro-5-hydroxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-fluoro-5-hydroxyphenylboronic acid (Combi-Blocks, San Diego, USA, 21 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.58 min (Method A); M+H=404 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 10.09 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.10-8.03 (m, 1H), 7.87-7.80 (m, 1H), 7.52-7.46 (m, 1H), 6.75-6.64 (m, 2H), 6.63-6.52 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H))

Example 34 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-hydroxy-5-trifluoromethyl-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-hydroxy-5-(trifluoromethyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 27 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.83 min (Method A); M+H=454 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 10.38 (s, br, 1H), 8.98 (s, 1H), 8.18 (s, 1H), 8.12-8.07 (m, 1H), 7.93-7.87 (m, 1H), 7.58-7.53 (m, 1H), 7.21-7.16 (m, 1H), 7.13-7.09 (m, 1H), 7.07-7.03 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 1.93 (s, 3H))

Example 35 8-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2,2-difluorobenzo[1,3]dioxole-4-boronic acid (Apollo, Cheshire, United Kingdom, 26 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.95 min (Method A); M+H=450 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.18-8.13 (m, 1H), 8.08 (s, 1H), 7.97-7.91 (m, 1H), 7.88-7.84 (m, 1H), 7.441-7.38 (m, 2H), 7.36-7.29 (m, 1H), 3.85 (s, 3H), 3.58 (s, 3H), 1.94 (s, 3H))

Example 36 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 7-azaindole-5-boronic acid pinacol ester (ABCR, Karlsruhe, Germany, 31 mg, 0.127 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.35 min (Method A); M+H=410 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.75 (s, br, 1H), 8.95 (s, 1H), 8.38-8.28 (m, 1H), 8.22-8.15 (m, 1H), 8.13-8.03 (m, 2H), 8.01-7.95 (m, 1H), 7.59-7.51 (m, 2H), 6.55-6.47 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Example 37.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-phenyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and phenylboronic acid (Aldrich, Buchs, Switzerland, 16.5 mg, 0.135 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.70 min (Method A); M+H=370 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.16 (s, 1H), 8.11-8.06 (m, 1H), 7.93-7.88 (m, 1H), 7.56-7.53 (m, 1H), 7.50-7.44 (m, 4H), 7.42-7.34 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using phenylboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 37.2 H

3-Methyl-8-phenyl-1- (1,3,5-trimethyl- 1H-pyrazol-4-yl)-1,3- dihydro-imidazo [4,5-c]quinolin-2- one 384 2.73 37.3 L

N,N-Dimethyl-2-[3- methyl-4-(3-methyl-2- oxo-8-phenyl-2,3- dihydro-imidazo[4,5- c]quinolin-1-yl)- pyrazol-1-yl]- acetamide 441 2.65 37.4 O

2-[3,5-Dimethyl-4-(3- methyl-2-oxo-8- phenyl-2,3-dihydro- imidazo[4,5- c]quinolin-1-yl)- pyrazol-1-yl]-N,N- dimethyl-acetamide 455 2.68

Example 38 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 3-quinolineboronic acid (Aldrich, Buchs, Switzerland, 22 mg, 0.127 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.40 min (Method A); M+H=421 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.03-8.96 (m, 2H), 8.52 (s, 1H), 8.21-7.99 (m, 5H), 7.83-7.76 (m, 1H), 7.75-7.71 (m, 1H), 7.71-7.65 (m, 1H), 3.95 (s, 3H), 3.59 (s, 3H), 1.98 (s, 3H))

Example 39 3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-benzenesulfonamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and methyl-3-boronobenzenesulfonamide (Combi-Blocks, San Diego, USA, 28 mg, 0.128 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.47 min (Method A); M+H=463 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.18-8.11 (m, 2H), 7.97-7.91 (m, 1H), 7.83-7.70 (m, 4H), 7.66-7.60 (m, 1H), 7.53-7.47 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 2.44 (s, 3H), 1.95 (s, 3H))

Example 40 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-methanesulfonyl-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and (3-methylsulfonylphenyl)boronic acid (Combi-Blocks, San Diego, USA, 26 mg, 0.127 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.45 min (Method A); M+H=448 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.19-8.11 (m, 2H), 8.02-7.97 (m, 1H), 7.95-7.86 (m, 3H), 7.80-7.74 (m, 1H), 7.64-7.60 (m, 1H), 3.93 (s, 3H), 3.59 (s, 3H), 3.33-3.30 (3H), 1.94 (s, 3H))

Example 41 4-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-benzamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and (3-methylsulfonylphenyl)boronic acid (Aldrich, Buchs, Switzerland, 21 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=413 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.15 (m, 1H), 8.14-8.08 (m, 1H), 8.07-8.01 (m, 1H), 7.99-7.93 (m, 3H), 7.61-7.52 (m, 3H), 7.47-7.39 (m, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H))

Example 42 8-(6-Cyclopropylmethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 6-(cyclopropylmethoxy)pyridine-3-boronic acid pinacol ester (ABCR, Karlsruhe, Germany, 36 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.88 min (Method A); M+H=441 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.29-8.23 (m, 1H), 8.16-8.04 (m, 2H), 7.92-7.85 (m, 1H), 7.80-7.72 (m, 1H), 7.49-7.43 (m, 1H), 6.98-6.90 (m, 1H), 4.15-4.09 (m, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H), 1.31-1.17 (m, 1H), 0.62-0.48 (m, 2H), 0.40-0.30 (m, 2H))

Example 43.1 4-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-benzamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 48 mg, 0.129 mmol) and 4-(N-methylaminocarbonyl)phenylboronic acid (ABCR, Karlsruhe, Germany, 27 mg, 0.153 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.40 min (Method A); M+H=427 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.54-8.48 (m, 1H), 8.19-8.15 (m, 1H), 8.13-8.07 (m, 1H), 7.98-7.89 (m, 3H), 7.61-7.53 (m, 3H), 3.94 (s, 3H), 3.57 (s, 3H), 2.79 (d, 3H), 1.95 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 4-(N-methylaminocarbonyl)phenylboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 43.2 K

4-[1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-3-methyl-2-oxo- 2,3-dihydro-1H- imidazol[4,5- c]quinolin-8-yl]-N- methyl-benzamide 447 2.47

Example 44 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-(pyrrolidinylsulfonyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 33 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.78 min (Method A); M+H=503 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.16-8.11 (m, 2H), 8.02-7.96 (m, 1H), 7.94-7.89 (m, 1H), 7.83-7.78 (m, 1H), 7.77-7.71 (m, 2H), 7.69-7.65 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.21-3.14 (m, 4H), 1.95 (s, 3H), 1.70-1.63 (m, 4H))

Example 45.1 8-(5-Amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-aminopyridine-5-boronic acid pinacol ester (Apollo Scientific, Cheshire, United Kingdom, 29 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: t_(R) 1.99 min (Method A); M+H=386 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.05 (m, 2H), 7.94-7.89 (m, 1H), 7.81-7.74 (m, 2H), 7.54-7.48 (m, 1H), 7.04-6.98 (m, 1H), 5.45 (s, br, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-aminopyridine-5-boronic acid pinacol ester and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 45.2 F

8-(5-Amino-pyridin-3- yl)-1-(1-ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 400 1.98 45.3 A

8-(5-Amino-pyridin-3- yl)-1-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 414 2.05

Example 46 3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-benzamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and benzamide-3-boronic acid (ABCR, Karlsruhe, Germany, 21 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.34 min (Method A); M+H=413 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.16 (m, 1H), 8.14-8.10 (m, 1H), 8.09-8.04 (m, 1H), 8.02-7.95 (m, 2H), 7.89-7.83 (m, 1H), 7.65-7.59 (m, 2H), 7.58-7.47 (m, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.93 (s, 3H))

Example 47 N-{3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-phenyl}-methanesulfonamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-(Methanesulfonylamino)phenylboronic acid (ABCR, Karlsruhe, Germany, 28 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.46 min (Method A); M+H=463 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.88 (s, 1H), 8.97 (s, 1H), 8.12-8.10 (m, 2H), 7.82-7.79 (m, 1H), 7.56-7.54 (m, 1H), 7.45-7.41 (m, 1H), 7.36-7.34 (m, 1H), 7.21-7.16 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 3.03 (s, 3H), 1.96 (s, 3H))

Example 48 4-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N,N-dimethyl-benzamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 25 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.51 min (Method A); M+H=441 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.17 (s, 1H), 8.12-8.10 (m, 1H), 7.96-7.93 (m, 1H), 7.59-7.58 (m, 1H), 7.55-7.50 (m, 4H), 3.93 (s, 3H), 3.58 (s, 3H), 2.99 (s, 3H), 2.94 (s, 3H), 1.95 (s, 3H))

Example 49 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (Combi-Blocks, San Diego, USA, 35 mg, 0.128 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.40 min (Method A); M+H=425 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 10.52 (s, 1H), 8.92 (s, 1H), 8.17 (s, 1H), 8.05-8.03 (m, 1H), 7.86-7.83 (m, 1H), 7.46 (s, 1H), 7.33-7.29 (m, 2H), 6.90-6.88 (m, 1H), 3.94 (s, 3H), 3.57 (s, 3H), 3.54 (s, 2H), 1.93 (s, 3H))

Example 50 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-2,3-dihydro-1H-indol-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 1-methylindoline-5-boronic acid pinacol ester (Maybridge, Basel, Switzerland, 34 mg, 0.127 mmol) to give the title compound as a yellow solid. (HPLC: t_(R) 2.52 min (Method A); M+H=425 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.87 (s, 1H), 8.16 (s, 1H), 8.00-7.97 (m, 1H), 7.83-7.81 (m, 1H), 7.41-7.40 (m, 1H), 7.20-7.17 (m, 1H), 7.14-7.13 (m, 1H), 6.57-6.55 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 3.33-3.29 (m, 2H), 2.92 (t, 2H), 2.73 (s, 3H), 1.94 (s, 3H))

Example 51.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4-pyrazol-1-yl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 4-(1H-pyrazol-1-yl)phenylboronic acid (Combi-Blocks, San Diego, USA, 24 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.79 min (Method A); M+H=436 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.60-8.56 (m, 1H), 8.19-8.15 (m, 1H), 8.13-8.07 (m, 1H), 7.99-7.93 (m, 3H), 7.80-7.75 (m, 1H), 7.63-7.56 (m, 3H), 6.59-6.53 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 1.1 using 4-(1H-pyrazol-1-yl)phenylboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 51.2 L

N,N-Dimethyl-2-{3- methyl-4-[3-methyl-2- oxo-8-(4-pyrazol-1-yl- phenyl)-2,3-dihydro- imidazo[4,5-c]quinolin- 1-yl]-pyrazol-1-yl}- acetamide 507 2.72 51.3 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-8-(4-pyrazol-1- yl-phenyl)-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 451 2.76 51.4 O

2-{3,5-Dimethyl-4-[3- methyl-2-oxo-8-(4- pyrazol-1-yl-phenyl)- 2,3-dihydro- imidazo[4,5-c]quinolin- 1-yl]pyrazol-1-yl}-N,N- dimethyl-acetamide 521 2.76 51.5 N

2-{3,5-Dimethyl-4-[3- methyl-2-oxo-8-(4- pyrazol-1-yl-phenyl)- 2,3-dihydro- imidazo[4,5-c]quinolin- 1-yl]pyrazol-1-yl}-N,N- dimethyl-acetamide 494 2.83 51.6 P

N-Ethyl-N-methyl-2-{3- methyl-4-[3-methyl-2- oxo-8-(4-pyrazol-1-yl- phenyl)-2,3-dihydro- imidazo[4,5-c]quinolin- 1-yl]pyrazol-1-yl}- acetamide 521 2.83

Example 52 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-ethoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 2-ethoxypyrimidine-5-boronic acid (Synthonix, Wake Forest, USA, 22 mg, 0.130 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.51 min (Method A); M+H=416 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.73-8.67 (m, 2H), 8.16-8.09 (m, 2H), 7.98-7.91 (m, 1H), 7.51-7.46 (m, 1H), 4.39 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.35 (t, 3H))

Example 53.1 3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N,N-dimethyl-benzenesulfonamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 3-(N,N-dimethylsulfonamide)phenylboronic acid (Combi-Blocks, San Diego, USA, 20 mg, 0.128 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.66 min (Method A); M+H=477 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.17-8.09 (m, 2H), 8.01-7.90 (m, 2H), 7.80-7.72 (m, 2H), 7.71-7.64 (m, 2H), 3.91 (s, 3H), 3.58 (s, 3H), 2.66 (s, 6H), 1.96 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 3-(N,N-dimethylsulfonamide)phenylboronic acid and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 53.2 H

N,N-Dimethyl-3-[3- methyl-2-oxo-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-2,3-dihydro-1H- imidazo[4,5- c]quinolin-8-yl]- benzenesulfonamide 491 2.70

Example 54.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 5-(methoxymethyl)pyridine-3-boronic acid pinacol ester (PepTeck, Burlington, USA, 32 mg, 0.128 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.08 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.70-8.67 (m, 1H), 8.56-8.54 (m, 1H), 8.19-8.13 (m, 2H), 8.02-7.98 (m, 1H), 7.82-7.80 (m, 1H), 7.62-7.59 (m, 1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.60 (s, 3H), 3.37 (s, 3H), 1.97 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 5-(methoxymethyl)pyridine-3-boronic acid pinacol ester and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 54.2 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(5- methoxymethyl- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 435 2.25

Example 55 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-propoxy-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-propoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 55.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.87 min (Method A); M+H=429 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.28 (s, 1H), 8.15-8.11 (m, 1H), 8.11-8.05 (m, 1H), 7.92-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.45 (m, 1H), 6.95-6.89 (m, 1H), 4.24 (t, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.78-1.68 (m, 2H), 0.98 (t, 3H))

Stage 55.1.1 2-Propoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-propoxypyridine (Combi-Blocks, San Diego, USA) to give the title compound as a brown oil. (HPLC: t_(R) 2.00 min (Method A); M+H=264 MS-ES).

Example 56.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 56.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.28 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.34-8.24 (m, 2H), 8.16-8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.61-7.57 (m, 1H), 7.40-7.34 (m, 1H), 4.17 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.40 (t, 3H))

Stage 56.1.1 3-Ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 3-bromo-5-ethoxypyridine (SynChem, Des Plaines, USA) to give the title compound as a brown oil. (HPLC: t_(R) 2.45 min (Method A); M+H=250 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 56.2 l

2-{4-[8-(5-Ethoxy- pyridin-3-yl)-3-methyl- 2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin- 1-yl]-3-methyl-pyrazol- 1-yl}-N,N-dimethyl- acetamide 486 2.30 56.3 H

8-(5-Ethoxy-pyridin-3- yl)-3-methyl-1-(1,3,5- trimethyl-1H-pyrazol-4- yl)-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 429 2.25 56.4 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(5- ethoxy-pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 435 2.40 56.5 I

1-(2,4-Dimethyl-2H- pyrazol-3-yl)-8-(5- ethoxy-pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5-c]quinolin- 2-one 415 2.36

Example 57 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-ethoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 3-ethoxyphenylboronic acid (Aldrich, Buchs, Switzerland, 21.4 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.84 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.16 (s, 1H), 8.09-8.06 (m, 1H), 7.94-7.91 (m, 1H), 7.57-7.59 (m, 1H), 7.39-7.35 (m, 1H), 7.12-6.92 (m, 3H), 4.09 (q, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.37 (t, 3H))

Example 58.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 58.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.30 min (Method A); M+H=429 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.33-8.28 (m, 1H), 8.28-8.23 (m, 1H), 8.16-8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.61-7.55 (m, 1H), 7.38-7.33 (m, 1H), 4.84-4.73 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.33 (d, 6H))

Stage 58.1.1 3-Isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 3-bromo-5-isopropoxypyridine (Stage 58.1.2) to give the title compound as a brown sticky solid. (HPLC: t_(R) 2.12 min (Method A); M+H=264 MS-ES).

Stage 58.1.2 3-Bromo-5-isopropoxypyridine

The title compound was synthesized in a similar manner as described for Stage 29.1.1 using 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland) and isopropanol (Merck, Dietikon, Switzerland) to give the title compound as a colorless oil. (HPLC: t_(R) 2.92 min (Method A); M+H=216, 218 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 58.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 58.2 K

1-(3-Chloro-1-methyl-1H- pyrazol-4-yl)-8-(5- isopropoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2- one 449 2.51 58.3 I

1-(2,4-Dimethyl-2H- pyrazol-3-yl)-8-(5- isopropoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one 429 2.47 58.4 F

1-(1-Ethyl-3-methyl-1H- pyrazol-4-yl)-8-(5- isopropoxy-pyridin-3-yl)- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one 443 2.38 58.5 P

N-Ethyl-2-{4-[8-(5- isopropoxy-pyridin-3-yl)- 3-methyl-2-oxo-2,3- dihydro-imidazo[4,5- c]quinolin-1-yl]-3-methyl- pyrazol-1-yl}-N-methyl- acetamide 514 2.41

Example 59.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 59.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.17 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.35-8.27 (m, 2H), 8.18-8.08 (m, 2H), 8.04-7.97 (m, 1H), 7.61-7.56 (m, 1H), 7.44-7.38 (m, 1H), 4.25 (t, 2H), 3.89 (s, 3H), 3.71 (t, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.96 (s, 3H))

Stage 59.1.1 3-(2-Methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 3-bromo-5-(2-methoxy-ethoxy)-pyridine (Stage 59.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 2.10 min (Method A)).

Stage 59.1.2 3-Bromo-5-(2-methoxy-ethoxy)-pyridine

A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 611 mg, 3.51 mmol), potassium carbonate (971 mg, 7.02 mmol) and 2-bromoethyl methyl ether (537 mg, 3.86 mmol) in 30 ml DMF was stirred for 14 h at rt and for 2 h at 80° C. The reaction mixture was quenched with water and extracted with EtOAc (2×). The organic layers were washed with brine (3×), dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (dichloromethane/MeOH 0% to 3%) to give the title compound as an oil. (HPLC: t_(R) 2.38 min (Method A); M+H=232, 234 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using 3-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 59.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 59.2 H

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-[5- (2-methoxy-ethoxy)- pyridin-3-yl]-3-methyl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 465 2.33

Example 60.1 8-(5-Cyclobutoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 60.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.43 min (Method A); M+H=441 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.32-8.30 (m, 1H), 8.24-8.20 (m, 1H), 8.15 (s, 1H), 8.14-8.10 (m, 1H), 8.00-7.95 (m, 1H), 7.58-7.56 (m, 1H), 7.26-7.24 (m, 1H), 4.84 (qt, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 2.53-2.45 (m, 2H), 2.15-2.00 (m, 2H), 1.96 (s, 3H), 1.88-1.66 (m, 2H))

Stage 60.1.1 3-Cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 58.1.1-2 using cyclobutanol (Aldrich, Buchs, Switzerland) to give the title compound as a brown oil. (HPLC: t_(R) 2.25 min (Method A); M+H=276 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using 3-cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 60.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 60.2 O

2-{4-[8-(5- Cyclobutoxy-pyridin- 3-yl)-3-methyl-2-oxo- 2,3-dihydro- imidazo[4,5- c]quinolin-1-yl]-3,5- dimethyl-pyrazol-1-yl}- N,N-dimethyl- acetamide 526 2.46

Example 61 8-(5-Cyclopropylmethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 60.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.39 min (Method A); M+H=441 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99-8.98 (m, 1H), 8.32-8.27 (m, 2H), 8.15 (s, 1H), 8.13-8.09 (m, 1H), 8.02-7.97 (m, 1H), 7.59-7.57 (m, 1H), 7.37-7.35 (m, 1H), 4.02-3.92 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.32-1.23 (m, 1H), 0.65-0.59 (m, 2H), 0.41-0.36 (m, 2H))

Stage 61.1.1 3-Cyclopropylmethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 58.1.1-2 using cyclopropylmethanol (Aldrich, Buchs, Switzerland) to give the title compound as a brown oil. (HPLC: t_(R) 2.25 min (Method A); M+H=276 MS-ES).

Example 62 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-pyridin-3-yl}-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide (Stage 62.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.52 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.40-8.31 (m, 1H), 8.18-8.06 (m, 2H), 8.03-7.90 (m, 1H), 7.86-7.71 (m, 1H), 7.55-7.43 (m, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.57 (s, 3H), 3.07 (s, 3H), 1.94 (s, 3H), 1.74 (s, 3H))

Stage 62.1.1 N-[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using N-(5-bromo-2-methoxy-pyridin-3-yl)-N-methyl-acetamide (Stage 62.1.2) to give the title compound as a brown solid. (HPLC: t_(R) 1.99 min (Method A); M+H=307 MS-ES).

Stage 62.1.2 N-(5-Bromo-2-methoxy-pyridin-3-yl)-N-methyl-acetamide

To N-(5-bromo-2-methoxy-pyridin-3-yl)-acetamide (Stage 62.1.3, 100 mg, 0.408 mmol) DMF (1 ml) was added NaH 55% in oil (19.6 mg, 0.45 mmol). The reaction mixture was stirred for 10 min at rt then was added MeI (0.031 ml, 0.49 mmol). The reaction mixture was stirred for 1 h at rt then quenched with brine and extracted with EtOAc (2×). The organic layers are washed with brine (3×), dried over Na₂SO₄, filtered and evaporated. The crude product was purified by Prep.HPLC. The fractions containing the product were collected together and basified with NaHCO₃, before being concentrated and extracted with EtOAc (3×). The organic layers were dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as an off-white solid (HPLC: t_(R) 2.75 min (Method A); M+H=259, 261 MS-ES).

Stage 62.1.3 N-(5-Bromo-2-methoxy-pyridin-3-yl)-acetamide

A suspension of 5-bromo-2-methoxy-3-nitro-pyridine (Stage 63.1.4, 450 mg, 1.93 mmol) and tin dichloride (1.465 mg, 7.72 mmol) in EtOAc (30 ml) was refluxed for 3 h. The reaction mixture was evaporated to dryness and then quenched with cold 3 M aqueous NaOH (50 ml) and CH₂Cl₂ (50 ml) and stirred for 3 h at rt. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with 30 ml sat. aqueous NaHCO₃, dried over Na₂SO₄, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (CH₂Cl₂/MeOH 0% to 4%) to give after evaporation the title compound as an off-white solid (HPLC: t_(R) 2.72 min (Method A); M+H=245, 247 MS-ES).

Stage 62.1.4 5-Bromo-2-methoxy-3-nitro-pyridine

In a vial are introduced 1 ml of MeOH and 50.8 mg (2.21 mmol) of Na. After dissolution of the metal, the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 500 mg, 2.11 mmol) in MeOH (2 ml). The reaction mixture is stirred for 1 h at 0° C. and for 15 h at rt, then concentrated and quenched with water. The precipitate was filtered, washed with water (2×) and dried under vacuum to give the title compound as a pale yellow solid (HPLC: t_(R) 3.06 min (Method A).

Example 63 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-ethoxy-pyridin-3-yl}-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide (Stage 63.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.64 min (Method A); M+H=486 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.40-8.28 (m, 1H), 8.18-8.06 (m, 2H), 8.04-7.91 (m, 1H), 7.85-7.69 (m, 1H), 7.54-7.41 (m, 1H), 4.52-4.33 (m, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.08 (s, 3H), 1.93 (s, 3H), 1.75 (s, 3H), 1.32 (t, 3H))

Stage 63.1.1 N-[2-Ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Stage 62.1.1-4 using ethanol as solvent and a sodium ethanolate solution to give the title compound as an off-white solid. (HPLC: t_(R) 2.21 min (Method A); M+H=3217 MS-ES).

Example 64 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-pyridin-3-yl}-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 64.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.51 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.52 (s, br, 1H), 8.96 (s, 1H), 8.50-8.41 (m, 1H), 8.15-8.09 (m, 2H), 8.06-8.02 (m, 1H), 7.88-7.83 (m, 1H), 7.55-7.49 (m, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.57 (s, 3H), 2.14 (s, 3H), 1.93 (s, 3H))

Stage 64.1.1 N-[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using N-(5-bromo-2-methoxy-pyridin-3-yl)-acetamide (Stage 62.1.3) to give the title compound as a beige solid. (HPLC: t_(R) 1.84 min (Method A); M+H=293 MS-ES).

Example 65 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-ethoxy-pyridin-3-yl}-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (synthesized in a similar manner as Stage 64.1.1, (HPLC: t_(R) 1.84 min (Method A); M+H=293 MS-ES)) to give the title compound as a white solid. (HPLC: t_(R) 2.64 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.37 (s, 1H), 8.96 (s, 1H), 8.45-8.43 (m, 1H), 8.12-8.08 (m, 2H), 8.01-8.00 (m, 1H), 7.85-7.82 (m, 1H), 7.52-7.50 (m, 1H), 4.44 (q, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 2.15 (s, 3H), 1.92 (s, 3H), 1.37 (t, 3H))

Example 66 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 66.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.62 min (Method A); M+H=446 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.72-8.66 (m, 1H), 8.46-8.39 (m, 1H), 8.18-8.10 (m, 2H), 8.05-7.96 (m, 1H), 7.58-7.53 (m, 1H), 4.07 (s, 3H), 3.91 (s, 3H), 3.59 (s, 3H), 1.94 (s, 3H))

Stage 66.1.1 2-Methoxy-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-methoxy-3-nitro-pyridine (Stage 62.1.4) to give the title compound as a brown solid. (HPLC: t_(R) 2.22 min (Method A); M+H=281 MS-ES).

Example 67 8-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1,3-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 67.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.39 min (Method A); M+H=455 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.07 (m, 3H), 7.99-7.94 (m, 1H), 7.58-7.53 (m, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 3.41 (s, 3H), 3.35 (s, 3H), 1.97 (s, 3H))

Stage 67.1.1 1,3-Dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-methoxy-3-nitro-pyridine (Stage 67.1.2) to give the title compound as an off-white solid. (HPLC: t_(R) 1.93 min (Method A); M+H=290 MS-ES).

Stage 67.1.2 6-Bromo-1,3-dimethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was synthesized in a similar manner as described for Intermediate A using 5-bromo-2-methoxy-3-nitro-pyridine (Stage 67.1.3) to give the title compound as a violet solid. (HPLC: t_(R) 2.63 min (Method A); M+H=242, 244 MS-ES).

Stage 67.1.3 6-Bromo-3-methyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was synthesized in a similar manner as described for Stage A.1 using 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4) to give the title compound as a gray solid. (HPLC: t_(R) 2.37 min (Method A); M+H=228, 230 MS-ES).

Stage 67.1.4 5-Bromo-N*2*-methyl-pyridine-2,3-diamine

A suspension of (5-bromo-3-nitro-pyridin-2-yl)-methyl-amine (Stage 67.1.5, 4.58 g, 19.75 mmol) and tin dichloride dihydrate (Acros, Basel, Switzerland, 13.38 g, 59.3 mmol) in 200 ml of THF was heated at 70° C. for 220 min. The solvent was removed by evaporation and the residue taken in CH₂Cl₂ (100 ml) and 5 M aqueous NaOH (50 ml) and stirred until all the solid was dissolved. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a brown solid. (HPLC: t_(R) 1.69 min (Method A); M+H=202, 204 MS-ES).

Stage 67.1.5 (5-Bromo-3-nitro-pyridin-2-yl)-methyl-amine

To a solution of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 9.8 g, 41.3 mmol) in 250 ml THF was added 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 12.9 ml, 103 mmol). The reaction mixture was stirred 1 h at rt then was quenched with 300 ml water. The precipite was filtered and the filtrate concentrated before being filtered again. The yellow solids were combined and dried to give the title compound as a yellow solid (HPLC: t_(R) 3.13 min (Method A)).

Example 68 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-ethyl-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 68.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.47 min (Method A); M+H=469 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.14-8.08 (m, 3H), 8.01-7.94 (m, 1H), 7.62-7.58 (m, 1H), 7.58-7.54 (m, 1H), 3.94 (q, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 3.37 (s, 3H), 1.97 (s, 3H), 1.28 (t, 3H))

Stage 68.1.1 1-Ethyl-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was synthesized in a similar manner as described for Stage 67.1.1-2 using ethyliodide (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 1.98 min (Method A); M+H=304 MS-ES).

Example 69 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-(2-methoxy-ethyl)-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 69.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.46 min (Method A); M+H=499 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.15-8.05 (m, 3H), 7.97-7.91 (m, 1H), 7.64-7.60 (m, 1H), 7.57-7.53 (m, 1H), 4.11-4.03 (m, 2H), 3.90 (s, 3H), 3.67-3.62 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H), 3.23 (s, 3H), 1.98 (s, 3H))

Stage 69.1.1 1-(2-Methoxy-ethyl)-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

The title compound was synthesized in a similar manner as described for Stage 67.1.1-2 using 2-bromoethyl methyl ether (Aldrich, Buchs, Switzerland) to give the title compound as a brown solid. (HPLC: t_(R) 2.03 min (Method A); M+H=334 MS-ES).

Example 70 8-(2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and dimethyl-[3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-amine (Stage 70.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.21 min (Method A); M+H=468 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.17-8.06 (m, 3H), 7.96-7.90 (m, 1H), 7.72-7.67 (m, 1H), 7.56-7.52 (m, 1H), 3.91 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 3.06 (s, 6H), 1.97 (s, 3H))

Stage 70.1.1 Dimethyl-[3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (6-bromo-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-dimethyl-amine (Stage 70.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 1.76 min (Method A); M+H=303 MS-ES).

Stage 70.1.2 (6-Bromo-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-dim ethyl-amine

A solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 2.09 g, 10.34 mmol) and dichloromethylene-dimethyliminium chloride (Aldrich, Buchs, Switzerland, 5.04 g, 31.0 mmol) in NMP (60 ml) was stirred for 17 h at rt. The reaction mixture was quenched with saturated aqueous NaHCO₃ and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated aqueous NaHCO₃ and with brine, then dried over Na₂SO₄, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-5%) to give the title compound as a red solid. (HPLC: t_(R) 2.13 min (Method A); M+H=255, 257 MS-ES).

Example 71 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 71.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.62 min (Method A); M+H=455 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.24-8.20 (m, 1H), 8.17-8.13 (m, 1H), 8.13-8.08 (m, 1H), 7.97-7.92 (m, 1H), 7.87-7.83 (m, 1H), 7.55-7.53 (m, 1H), 4.16 (s, 3H), 3.91 (s, 3H), 3.57 (s, 6H), 1.97 (s, 3H))

Stage 71.1.1 2-Methoxy-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 6-bromo-2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine (Stage 71.1.2) to give the title compound as a yellow solid. (HPLC: t_(R) 1.94 min (Method A); M+H=290 MS-ES).

Stage 71.1.2 6-Bromo-2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine

A solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 960 mg, 4.75 mmol) and tetramethylorthocarbonate (Aldrich, Buchs, Switzerland, 2 ml, 14.7 mmol) and acetic acid (0.273 ml, 4.75 mmol) was stirred for 90 min at 100° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO₃ and brine. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated aqueous NaHCO₃ and with brine, then dried over Na₂SO₄, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-4%) to give the title compound as a green solid. (HPLC: t_(R) 2.83 min (Method A); M+H=242, 244 MS-ES).

Example 72 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 72.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.43 min (Method A); M+H=426 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.86-8.81 (m, 1H), 8.65-8.61 (m, 1H), 8.21-8.13 (m, 2H), 8.10-8.04 (m, 1H), 7.63-7.59 (m, 1H), 4.33 (s, 3H), 3.92 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))

Stage 72.1.1 3-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 6-bromo-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Stage 72.1.2) to give the title compound as a yellow solid. (HPLC: t_(R) 1.85 min (Method A); M+H=261 MS-ES).

Stage 72.1.2 6-Bromo-3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine

To a solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 1.2 g, 5.94 mmol) in 2 M aqueous HCl (70 ml) cooled with an ice-bath was added a solution of sodium nitrite (Fluka, Buchs, Switzerland, 492 mg, 7.13 mmol) in water (10 ml). The reaction mixture was stirred at 0° C. for 1 h and at rt for 75 min then basified with 2 M aqueous NaOH (75 ml) and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0%-30%) to give the title compound as a blue solid. (HPLC: t_(R) 2.46 min (Method A); M+H=213, 215 MS-ES).

Example 73 8-(2,3-Dimethyl-3H-imidazo[4,5-b]pyridin-6-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (stage 73.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.20 min (Method A); M+H=439 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.41-8.38 (m, 1H), 8.18-8.15 (m, 1H), 8.13-8.09 (m, 1H), 8.02-7.96 (m, 2H), 7.58-7.54 (m, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.58 (s, 3H), 2.59 (s, 3H), 1.97 (s, 3H))

Stage 73.1.1 2,3-Dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine

The title compound was synthesized in a similar manner as described for stage 5.1.1 using 6-bromo-2,3-dimethyl-3H-imidazo[4,5-b]pyridine (stage 73.1.2) to give the title compound as a green solid. (HPLC: t_(R) 1.51 min (Method A); M+H=274 MS-ES).

Stage 73.1.2 6-Bromo-2,3-dimethyl-3H-imidazo[4,5-b]pyridine

A solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 960 mg, 4.75 mmol) in triethylorthoacetate (Aldrich, Buchs, Switzerland, 25 ml) was stirred for 38.5 h at 140° C. The reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO₃. The aqueous layer was extracted with EtOAc and the combined organic layers washed with brine, dried over Na₂SO₄, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-4%) to give the title compound as a brown solid. (HPLC: t_(R) 1.95 min (Method A); M+H=226, 228 MS-ES).

Example 74 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 74.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.26 min (Method A); M+H=425 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.52-8.46 (m, 2H), 8.20-8.08 (m, 3H), 8.05-7.98 (m, 1H), 7.60-7.55 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Stage 74.1.1 3-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine

The title compound was synthesized in a similar manner as described for Stage 73.1.1-2 using triethylorthoformate (Aldrich, Buchs, Switzerland) to give the title compound as a brown solid. (HPLC: t_(R) 1.39 min (Method A); M+H=260 MS-ES).

Example 75 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methyl-pyridin-3-yl}-N-methyl-methanesulfonamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-methyl-N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 75.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.19 min (Method A); M+H=492 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.55-8.51 (m, 1H), 8.16-8.10 (m, 2H), 8.03-7.97 (m, 1H), 7.95-7.91 (m, 1H), 7.60-7.56 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.23 (s, 3H), 3.16 (s, 3H), 2.53 (s, 3H), 1.96 (s, 3H))

Stage 75.1.1 N-Methyl-N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 6-bromo-2,3-dimethyl-3H-imidazo[4,5-b]pyridine (Stage 75.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 2.15 min (Method A); M+H=327 MS-ES).

Stage 75.1.2 N-(5-Bromo-2-methyl-pyridin-3-yl)-N-methyl-methanesulfonamide

The title compound was synthesized in a similar manner as described for Stage 62.1.2 using N-(5-bromo-2-methyl-pyridin-3-yl)-methanesulfonamide (Stage 75.1.2) to give the title compound as a brownish solid. (HPLC: t_(R) 2.28 min (Method A); M+H=279, 281 MS-ES).

Stage 75.1.3 N-(5-Bromo-2-methyl-pyridin-3-yl)-methanesulfonamide

To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 573 mg, 3.06 mmol) in pyridine (6 ml) was added dropwise methansulfonyl chloride (Aldrich, Buchs, Switzerland, 0.286 ml, 3.68 mmol). The reaction mixture was stirred for 18 h at rt then are added methansulfonyl chloride (0.03 ml, 0.39 mmol). The reaction mixture was stirred 4 h at rt before being evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-5%) to give the title compound as a pinkish solid. (HPLC: t_(R) 2.05 min (Method A); M+H=265, 267 MS-ES).

Stage 75.1.4 5-Bromo-2-methyl-pyridin-3-ylamine

To a solution of 5-bromo-2-methyl-3-nitro-pyridine (stage 75.1.5, 765 mg, 3.53 mmol) in acetic acid (7 ml) and water (1.75 ml) was added in three portions iron powder (591 mg, 10.6 mmol). The reaction mixture was stirred for 2.5 h at rt then quenched with 20 ml of 10 M aqueous NaOH, 20 g ice and 20 ml EtOAc before being filtered over Celite. The solid was washed with EtOAc and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a gray solid. (HPLC: t_(R) 1.52 min (Method A); M+H=187, 189 MS-ES).

Stage 75.1.5 5-Bromo-2-methyl-3-nitro-pyridine

To a suspension of NaH 55% in oil (300 mg, 6.87 mmol) in 6 ml DMF was added dropwise diethyl malonate (Aldrich, Buchs, Switzerland, 1.0 g, 6.24 mmol). The reaction mixture was stirred for 20 min at rt before adding 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 1.19 g, 5.0 mmol). The reaction mixture was stirred for 30 min at rt and for 1 h at 40° C. The reaction mixture was quenched with 10% aqueous NH₄Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine (4×), dried over Na₂SO₄, filtered and evaporated. The residue was stirred in concentrated HCl (20 ml) for 13 h at 100° C. After cooling, the reaction mixture was basified with 10 M aqueous NaOH and extracted with EtOAc (2×). The organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0% to 15%) to give the title compound as a yellow solid. (HPLC: t_(R) 2.84 (Method A).

Example 76 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methyl-pyridin-3-yl}-methanesulfonamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 76.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.06 min (Method A); M+H=478 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.51-9.47 (m, 1H), 8.98 (s, 1H), 8.46-8.42 (m, 1H), 8.15-8.09 (m, 2H), 7.94-7.88 (m, 1H), 7.72-7.68 (m, 1H), 7.60-7.56 (m, 1H), 3.90 (s, 3H), 3.57 (s, 3H), 3.09 (s, 3H), 3.54 (s, 3H), 1.95 (s, 3H))

Stage 76.1.1 N-[2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using N-(5-bromo-2-methyl-pyridin-3-yl)-methanesulfonamide (Stage 75.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 1.96 min (Method A); M+H=313 MS-ES).

Example 77 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[4-(1H-imidazol-2-yl)-phenyl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 77.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.15 min (Method A); M+H=436 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 12.58 (s, br, 1H), 8.96 (s, 1H), 8.20-8.15 (m, 1H), 8.14-8.07 (m, 1H), 8.05-7.94 (m, 3H), 7.63-7.53 (m, 3H), 7.31-7.07 (m, br, 2H), 3.95 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H))

Stage 77.1.1 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-(4-bromo-phenyl)-1H-imidazole (Chem-Impex, Cogliate, Italy) to give the title compound as a brown oil. (HPLC: t_(R) 1.67 min (Method A); M+H=271 MS-ES).

Example 78 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(2-methyl-imidazol-1-yl)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-(2-methyl-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 78.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.10 min (Method A); M+H=451 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.68-8.66 (m, 1H), 8.18-8.13 (m, 2H), 8.09-8.00 (m, 2H), 7.78-7.74 (m, 1H), 7.63-7.59 (m, 2H), 6.94-6.93 (m, 1H), 3.93 (s, 3H), 3.59 (s, 3H), 2.54 (s, 3H), 1.96 (s, 3H))

Stage 78.1.1. 2-(2-Methyl-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-(2-methyl-imidazol-1-yl)-pyridine (Stage 78.1.2) to give the title compound as a brown solid. (HPLC: t_(R) 1.57 min (Method A); M+H=286 MS-ES).

Stage 78.1.2. 5-Bromo-2-(2-methyl-imidazol-1-yl)-pyridine

A mixture of 5-bromo-2-chloro-pyridine (Aldrich, Buchs, Switzerland, 392 mg, 2.04 mmol), 2-methyl-1H-imidazole (Aldrich, Buchs, Switzerland, 251 mg, 3.06 mmol) and ceasium carbonate (1.33 g, 4.08 mmol) in DMA (10 ml) was heated by microwave irradiation for 20 min at 100° C. and 2.5 h at 150° C. The reaction mixture was quenched with diluted brine (200 ml) and cooled. The precipitate was filtered, washed with water and dried to give the tilte compound as off-white solid. (HPLC: t_(R) 2.03 min (Method A); M+H=238, 240 MS-ES).

Example 79 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-pyrazol-1-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-pyrazol-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 79.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.64 min (Method A); M+H=437 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.68-8.66 (m, 1H), 8.59-8.57 (m, 1H), 8.16-8.12 (m, 2H), 8.10-7.98 (m, 3H), 7.87-7.85 (m, 1H), 7.60-7.58 (m, 1H), 6.62-6.59 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Stage 79.1.1. 2-Pyrazol-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-pyrazol-1-yl-pyridine (Combi-Blocks, San Diego, USA) to give the title compound as a brown solid. (HPLC: t_(R) 2.19 min (Method A); M+H=272 MS-ES).

Example 80.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(2-methylamino-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 80.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.18 min (Method A); M+H=401 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.49-8.34 (s, br, 2H), 8.13-8.11 (m, 1H), 8.07-8.04 (m, 1H), 7.89-7.85 (m, 1H), 7.42-7.37 (m, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 2.84 (d, 3H), 1.96 (s, 3H))

Stage 80.1.1. Methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-pyrimidin-2-yl)-methyl-amine (Combi-Blocks, San Diego, USA) to give the title compound as a beige solid. (HPLC: t_(R) 1.20 min (Method A); M+H=236 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 80.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 80.2 H

3-Methyl-8-(2- methylamino- pyrimidin-5-yl)-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3)- dihydro-imidazo[4,5- c]quinolin-2-one 415 2.27

Example 81.1 8-(2-Amino-pyrimidin-5-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.04 min (Method A); M+H=387 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.37 (s, 2H), 8.14-8.12 (m, 1H), 8.07-8.03 (m, 1H), 7.90-7.86 (m, 1H), 7.41-7.38 (m, 1H), 6.93 (s, br, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 81.2 H

8-(2-Amino-pyrimidin- 5-yl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 401 2.13

Example 82 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-isopropoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxyphenylboronic acid (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 2.95 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.19-8.16 (m, 1H), 8.09-8.05 (m, 1H), 7.94-7.89 (m, 1H), 7.57-7.54 (m, 1H), 7.39-7.33 (m, 1H), 7.10-7.06 (m, 1H), 6.94-9-6.90 (m, 2H), 4.68 (hp, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.30 (t, 6H))

Example 83 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-fluoro-3-isopropoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-fluoro-3-isopropoxyphenylboronic acid (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.91 min (Method A); M+H=446 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.11-8.07 (m, 2H), 7.77-7.73 (m, 1H), 7.56-7.54 (m, 1H), 7.22-7.15 (m, 2H), 6.99-6.92 (m, 1H), 4.64 (hp, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 1.94 (s, 3H), 1.33-1.28 (m, 6H))

Example 84.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 84.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=443 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.17-8.16 (m, 1H), 8.13-8.09 (m, 2H), 8.00-7.96 (m, 1H), 7.59-7.57 (m, 1H), 7.31-7.29 (m, 1H), 4.74 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.36 (s, 3H), 1.97 (s, 3H), 1.35 (t, 6H))

Stage 84.1.1. 3-Isopropoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-3-isopropoxy-2-methyl-pyridine (Stage 84.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 2.21 min (Method A); M+H=278 MS-ES).

Stage 84.1.2. 5-Bromo-3-isopropoxy-2-methyl-pyridine

To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 400 mg, 2.13 mmol) in isopropanol (33 ml) were added 4 M HCl in dioxane (0.535 ml, 2.13 mmol) and isoamyl nitrite (1.25 g, 10.7 mmol). The reaction mixture was heated at 80° C. for 2.5 h, before being evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO₃. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na₂SO₄, filtered and evaporated. The residue was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0% to 30%) to give the title compound as an orange oil (HPLC: t_(R) 2.47 min (Method A); M+H=230, 232 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using 3-isopropoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 84.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 84.2 F

1-(1-Ethyl-3-methyl-1H- pyrazol-4-yl)-8-(5- isopropoxy-6-methyl- pyridin-3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 457 2.38

Example 85.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 85.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.22 min (Method A); M+H=429 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.17 (m, 1H), 8.13-8.09 (m, 2H), 8.02-7.98 (m, 1H), 7.61-7.59 (m, 1H), 7.30-7.28 (m, 1H), 4.20-4.12 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 2.39 (s, 3H), 1.97 (s, 3H), 1.43 (t, 3H))

Stage 85.1.1. 3-Ethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner are described for Stage 84.1.1-2 using ethanol instead of isopropanol. (HPLC: t_(R) 2.03 min (Method A); M+H=264 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-ethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 85.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 85.2 N

8-(5-Ethoxy-6-methyl- pyridin-3-yl)-1-[1-(2- methoxy-ethyl)-3,5- dimethyl-1H-pyrazol-4-yl]- 3-methyl-1,3-dihydro- imidazo[4,5-c]quinolin-2- one 487 2.33 85.3 O

2-{4-[8-(5-Ethoxy-6- methyl-pyridin-3-yl)-3- methyl-2-oxo-2,3-dihydro- imidazo[4,5-c]quinolin-1- yl]-3,5-dimethyl-pyrazol-1- yl}-N,N-dimethyl- acetamide 514 2.30

Example 86.1 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-[5-(2-methoxy-ethoxy)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-methoxy-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 86.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.33 min (Method A); M+H=479 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.38 (s, 1H), 8.22-8.20 (m, 1H), 8.15-8.12 (m, 1H), 8.03-8.00 (m, 1H), 7.58-7.57 (m, 1H), 7.39-7.37 (m, 1H), 4.30-4.19 (m, 2H), 3.97 (s, 3H), 3.76 (t, 2H), 3.60 (s, 3H), 3.36 (s, 3H), 2.40 (s, 3H))

Stage 86.1.1. 3-(2-Methoxy-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner are described for Stage 84.1.1-2 using 2-methoxyethanol instead of isopropanol. (HPLC: tR 2.05 min (Method A); M+H=294 MS-ES)

The following example was synthesized in a similar manner as described for Example 1.1 using 3-(2-methoxy-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 86.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 86.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-[5-(2- methoxy-ethoxy)-6- methyl-pyridin-3-yl]-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 459 2.15

Example 87.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 87.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.18 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.95-7.91 (m, 1H), 7.88-7.86 (m, 1H), 7.61-7.59 (m, 1H), 6.78-6.76 (m, 1H), 5.23 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.21-3.14 (m, 2H), 2.33 (s, 3H), 1.97 (s, 3H), 1.25 (t, 3H))

Stage 87.1.1. Ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-2-methyl-pyridin-3-yl)-ethyl-amine (Stage 87.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 1.85 min (Method A); M+H=263 MS-ES).

Stage 87.1.2. (5-Bromo-2-methyl-pyridin-3-yl)-ethyl-amine

A solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 300 mg, 1.604 mmol), acetaldehyde (Fluka, Buchs, Switzerland, 71 mg, 1.6 mmol) in dichloromethane (30 ml) was stirred for 1.5 h at rt in presence of acetic acid (0.3 ml, 5.24 mmol). Was added sodium triacetoxyborohydride (850 mg, 4.01 mmol) and the reaction mixture was stirred 4 h at rt, then was added acetaldehyde (45 mg, 1.02 mmol) twice at 1.5 h interval and the reaction was stirred at rt for 15 h before being quenched with aqueous saturated NaHCO₃ and extracted with dichloromethane (2×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to dryness. (HPLC: t_(R) 2.08 min (Method A); M+H=215, 217 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 87.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 87.2 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(5- ethylamino-6-methyl- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 448 2.35 87.3 F

8-(5-Ethylamino-6- methyl-pyridin-3-yl)-1- (1-ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 442 2.22 87.4 N

8-(5-Ethylamino-6- methyl-pyridin-3-yl)-1- [1-(2-methoxy-ethyl)- 3,5-dimethyl-1H- pyrazol-4-yl]-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 486 2.26 87.5 O

2-{4-[8-(5-Ethylamino- 6-methyl-pyridin-3-yl)- 3-methyl-2-oxo-2,3- dihydro-imidazo[4,5- c]quinolin-1-yl]-3,5- dimethyl-pyrazol-1-yl}- N,N-dimethyl- acetamide 513 2.25

Example 88.1 8-(5-Amino-6-methyl-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (Stage 88.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.14 min (Method A); M+H=420 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.38 (s, 1H), 8.13-8.10 (m, 1H), 7.80-7.77 (m, 1H), 7.75-7.73 (m, 1H), 7.48-7.47 (m, 1H), 7.08-7.06 (m, 1H), 5.21-5.16 (m, br, 2H), 3.99 (s, 3H), 3.59 (s, 3H), 2.30 (s, 3H))

Stage 88.1.1. 2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine

The title compound was synthesized in a similar manner as described for stage 5.1.1 using 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4) to give the title compound as a brown oil. (HPLC: t_(R) 1.30 min (Method A); M+H=235 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using 3-(2-methoxy-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 86.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 88.2 A

8-(5-Amino-6-methyl- pyridin-3-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 400 2.01

Example 89 8-(5-Amino-6-methoxy-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (Stage 89.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.45 min (Method A); M+H=436 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.38 (s, 1H), 8.11-8.07 (m, 1H), 7.80-7.75 (m, 1H), 7.48-7.42 (m, 2H), 7.03-7.00 (m, 1H), 5.15-5.07 (s, br, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H))

Stage 89.1.1. 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-methoxy-pyridin-3-ylamine (Stage 89.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 1.10 min (Method A); M+H=251 MS-ES).

Stage 89.1.2. 5-Bromo-2-methoxy-pyridin-3-ylamine

The title compound was synthesized in a similar manner as described for Stage 67.1.4 using 5-Bromo-2-methoxy-3-nitro-pyridine (Stage 62.1.4) to give the title compound as an off-white solid. (HPLC: t_(R) 2.51 min (Method A); M+H=203, 205 MS-ES).

Example 90.1 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and ethyl-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (stage 90.1.1, 0.138 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.45 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.24-8.16 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.94 (m, 1H), 7.66-7.59 (m, 1H), 7.09-7.02 (m, 1H), 6.87-6.80 (m, 1H), 4.32 (q, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.34 (t, 3H))

Stage 90.1.1. Ethyl-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 87.1.1-2 using 5-bromo-2-methoxy-pyridin-3-ylamine (Stage 89.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 1.75 min (Method A); M+H=279 MS-ES)

The following example was synthesized in a similar manner as described for Example 1.1 using ethyl-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 90.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 90.2 N

8-(5-Ethylamino-6- methoxy-pyridin-3-yl)- 1-[1-(2-methoxy- ethyl)-3,5-dimethyl- 1H-pyrazol-4-yl]-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 502 2.74

Example 91 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-ethoxy-pyridin-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-ethoxy-4-pyridinylboronic acid (Combi-Blocks, San Diego, USA, 22.4 mg, 0.134 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.45 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.24-8.16 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.94 (m, 1H), 7.66-7.59 (m, 1H), 7.09-7.02 (m, 1H), 6.87-6.80 (m, 1H), 4.32 (q, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 1.96 (s, 3H), 1.34 (t, 3H))

Example 92 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-isopropoxy-pyridin-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-Isopropoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 92.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.56 min (Method A); M+H=429 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.23-8.19 (m, 2H), 8.14-8.09 (m, 1H), 8.00-7.96 (m, 1H), 7.64-7.62 (m, 1H), 7.05-7.02 (m, 1H), 6.80-6.78 (m, 1H), 5.28 (hp, 2H), 3.96 (s, 3H), 3.59 (s, 3H), 1.94 (s, 3H), 1.34-1.29 (m, 6H))

Stage 92.1.1. 2-Isopropoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 4-bromo-2-isopropoxy-pyridine (Stage 92.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 2.36 min (Method A); M+H=264 MS-ES)

Stage 92.1.2. 4-Bromo-2-isopropoxy-pyridine

To isopropanol (12 ml) under Ar was added 55% sodium hydride in oil (343 mg, 7.86 mmol) in two portions. After 30 min stirring at rt was added 4-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland, 1.01 g, 5.24 mmol) and the reaction mixture was heated with microwave irradiation to 150° C. for 30 min. The reaction mixture was concentrated, quenched with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated. The crude product was purified by MPLC (heptane/EtOAc 0% to 20%) to give the title compound as an oil. (HPLC: t_(R) 3.58 min (Method A); M+H=216, 218 MS-ES)

Example 93 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 93.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.73 min (Method A); M+H=459 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.97-7.93 (m, 1H), 7.92-7.90 (m, 1H), 7.53-7.51 (m, 1H), 7.23-7.21 (m, 1H), 4.70 (hp, 2H), 3.89 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.98 (s, 3H), 1.36-1.30 (m, 6H))

Stage 93.1.1. 3-Isopropoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5- or 6-bromo-3-isopropoxy-2-methoxy-pyridine mixture (Stage 93.1.2) to give the title compound as an orange oil after silica gel flash chromatography purification (CH₂Cl₂/iPrOH 0% to 3.5%). (HPLC: t_(R) 2.24 min (Method A); M+H=294 MS-ES)

Stage 93.1.2. 5- or 6-Bromo-3-isopropoxy-2-methoxy-pyridine

To a solution at 10° C. of 3-Isopropoxy-2-methoxy-pyridine (Stage 93.1.3, 865 mg, 5.17 mmol) and potassium acetate (635 mg, 6.47 mmol) in acetic acid (4 ml) was added over 1.5 h a solution of bromine (1.1 g, 6.88 mmol) in acetic acid (2 ml). The reaction was stirred for 1 h at rt an then basified with 20% aqueous NaOH and extracted with EtOAc (2×). The organic layers were washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered and evaporated. The crude product is purified by flash chromatography (hexane/EtOAc 40:1 to 15:1) to give the title compounds as an oil (1:2). (HPLC: t_(R) 3.55 min (Method A); M+H=246, 248 MS-ES)

Stage 93.1.3. 3-Isopropoxy-2-methoxy-pyridine

To a solution of methanolate obtained by dissolving sodium (534 mg, 23.25 mmol) in MeOH (8 ml) was added a solution of 2-chloro-3-isopropoxy-pyridine (Stage 93.1.4, 1.14 g, 6.64 mmol) in MeOH (2 ml). The reaction mixture was heated at 150° C. by microwave irradiation for 25 min then concentrated and quenched with EtOAc and brine. The organic layer was dried over Na₂SO₄, filtered and evaporated to give the title compound as an oil (HPLC: t_(R) 2.66 min (Method A); M+H=264 MS-ES)

Stage 93.1.4. 2-Chloro-3-isopropoxy-pyridine

The title compound was synthesized in a similar manner as described for Stage 29.1.1 using 2-chloro-3-hydroxypyridine (Aldrich, Buchs, Switzerland). The crude product obtained was bulb-to-bulb distilled (160° C., ˜0.1 mmbar) and then purified by MPLC (heptane/EtOAc 0% to 35%) to give the title compound as an oil. (HPLC: t_(R) 2.97 min (Method A); M+H=172 MS-ES)

Example 94 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 92.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.63 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.98-7.94 (m, 1H), 7.92-7.90 (m, 1H), 7.54-7.53 (m, 1H), 7.22-7.21 (m, 1H), 4.16-4.09 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.41 (t, 3H))

Stage 94.1.1. 3-Ethoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 93.1.1-4 using isopropanol as replacement for ethanol to give the title compound as a brown oil. (HPLC: t_(R) 2.09 min (Method A))

Example 95 8-(5-Diethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and diethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 95.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.13-8.09 (m, 2H), 8.07-8.05 (m, 1H), 7.96-7.91 (m, 2H), 7.60-7.58 (m, 1H), 6.95-6.92 (m, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 3.46-3.39 (m, 4H), 1.97 (s, 3H), 1.13 (t, 6H))

Stage 95.1.1. Diethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-pyridin-3-yl)-diethyl-amine (Stage 95.1.2) to give the title compound as a brown oil. (HPLC: t_(R) 2.14 min (Method A); M+H=277 MS-ES)

Stage 91.1.2. (5-Bromo-pyridin-3-yl)-diethyl-amine

A solution of 3-amino-5-bromopyridine (Aldrich, Buchs, Switzerland, 400 mg, 2.31 mmol), acetic acid (0.4 ml, 6.99 mmol) and acetaldehyde (Fluka, Buchs, Switzerland, 153 mg, 3.47 mmol) in dichloromethane was stirred for 1.5 h at rt then was added sodium triacetoxyborohydride (980 mg, 4.62 mmol). The reaction mixture was stirred 17.5 h at rt then were added at 1.5 h interval acetaldehyde (153 mg, 3.47 mmol) and sodium tracetoxyborohydride (490 mg, 2.31 mmol). The RM was stirred 7 h at rt then were added at 1.5 h interval acetaldehyde (77 mg, 1.75 mmol) and sodium tracetoxyborohydride (490 mg, 2.31 mmol). After 15 h stirring at rt, the reaction mixture was diluted with dichloromethane and quenched with saturated aqueous NaHCO₃. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over Na₂SO₄, filtered and evaporated. The crude product was purified by flash chromatography (DCM/iPrOH 1% to 3.5%) to give the title compound as a yellowish oil. (HPLC: t_(R) 2.31 min (Method A); M+H=229, 231 MS-ES)

Example 96 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-(4-methylpiperazine-1-yl)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 40 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.04 min (Method A); M+H=469 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.30-8.24 (m, 1H), 8.14-8.10 (m, 1H), 8.07-8.01 (m, 1H), 7.90-7.83 (m, 1H), 7.62-7.56 (m, 1H), 7.45-7.41 (m, 1H), 6.97-6.90 (m, 1H), 3.92 (s, 3H), 3.55 (s, 7H), 2.41-2.35 (m, 4H), 2.21 (s, 3H), 1.95 (s, 3H))

Example 97 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-pyrrolidin-1-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-pyrrolidin-1-ylpyridine-5-boronic acid pinacol ester (Boron Molecular, Research Triangle Park, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.23 min (Method A); M+H=440 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.25-8.23 (m, 1H), 8.13-8.11 (m, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.58-7.53 (m, 1H), 7.42-7-40 (m, 1H), 6.56-6.52 (m, 1H), 3.92 (s, 3H), 3.56 (s, 3H), 3.44-3.38 (m, 4H), 1.97-1.92 (m, 7H))

Example 98.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(ethyl-methyl-amino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (stage 98.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.18 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.26-8.24 (m, 1H), 8.14-8.12 (m, 1H), 8.04-8.01 (m, 1H), 7.88-7.84 (m, 1H), 7.57-7.52 (m, 1H), 7.43-7-40 (m, 1H), 6.73-6.69 (m, 1H), 3.93 (s, 3H), 3.62-3.53 (m, 5H), 3.01 (s, 3H), 1.96 (s, 3H), 1.07 (t, 3H))

Stage 98.1.1. Ethyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1-2 using methylethylamine (Aldrich, Buchs, Switzerland) to give the title compound as a brown solid. (HPLC: t_(R) 1.77 min (Method A); M+H=263 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using ethyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 98.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 98.2 G

8-[6-(Ethyl-methyl- amino)-pyridin-3-yl]-1- (1-isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 456 2.31 98.3 F

8-[6-(Ethyl-methyl- amino)-pyridin-3-yl]-1- (1-ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 442 2.25

Example 99 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (PepTech, Burlington, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.03 min (Method A); M+H=410 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.52 (s, 1H), 8.96 (s, 1H), 8.43-8.41 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.10 (m, 1H), 8.00-7.95 (m, 1H), 7.83-7.81 (m, 1H), 7.72-7.69 (m, 1H), 7.60-7.58 (m, 1H), 6.60-6.58 (m, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Example 100 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid methyl ester

A mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol), 2-methylcarboxypyridine-5-boronic acid pinacol ester (aalen Chemical, Nanjing, China, 49 mg, 0.186 mmol), potassium fluoride (22 mg, 0.379 mmol), Pd₂(dba)₃ (7.7 mg, 0.0085 mmol) and tri-t-butylphosphonium tetrafluoroborate (4.9 mg, 0.017 mmol) in dioxane (0.6 ml) was stirred under argon in a sealed microwave tube at rt for 20 h. The reaction was not completed. Therefore, again Pd₂(dba)₃ (7.7 mg, 0.0085 mmol) and tri-t-butylphosphonium tetrafluoroborate (4.9 mg, 0.017 mmol) and 2-methylcarboxypyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 15 mg, 0.186 mmol) were added, the mixture was flushed with argon and stirred at rt for further 23 h. The RM was diluted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was dissolved in MeOH and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 60:30). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.45 min (Method A); M+H=429 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.83-8.78 (m, 1H), 8.20-8.12 (m, 3H), 8.11-8.06 (m, 1H), 8.05-7.98 (m, 1H), 7.69-7.62 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))

Example 101 {4-[8-(6-Methoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-acetic acid

A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.1b, 161 mg, 0.387 mmol), 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 77 mg, 0.503 mmol), and PdCl₂(PPh₃)₂ (17 mg, 0.024 mmol) in DMF (4.0 ml) and 1 M aqueous K₂CO₃ (1.16 ml) was stirred under argon at 105° C. for 1.25 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing products were collected together concentrated, before being lyophilized to give the title compound as a TFA-salt and white powder. (HPLC: t_(R) 2.38 min (Method A); M+H=446 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.22 (s, 1H), 8.46 (s, 1H), 8.23-8.14 (m, 3H), 7.87-7.79 (m, 1H), 7.74-7.68 (m, 1H), 6.94-6.88 (m, 1H), 5.15-4.98 (m, 2H), 3.89 (s, 3H), 3.60 (s, 3H), 1.97 (s, 3H))

Stage 101.1.1b [4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid

To a mixture of [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.2, 422 mg, 1.050 mmol) in DMF (6 ml) cooled to 0° C. was added NaH 55% (92 mg, 2 mmol). The cooling bath was removed and the RM was stirred for 45 min at it. Then iodomethane (0.132 ml, 2 mmol) was added and the RM was stirred for 1 h. The reaction was not completed. Therefore again NaH 55% (50 mg, 1.2 mmol) was added and stirred for 15 min and after that iodomethane (0.070 ml, 1.2 mmol) was added and stirred at rt for one further hour. Then the RM was quenched with saturated aqueous NaHCO₃ and extracted with EtOAc (2×) in the organic layer was found the ester side product: [4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.1a).

The aqueous layer was adjusted with 4 M aqueous HCl to pH 5. The mixture was then extracted with n-butanol (2×). The combined organic layer was evaporated. The residue was diluted with DCM/MeOH. The mixture was filtered over celite, and the filtrate was evaporated to give the title compound as a orange sticky solid. (HPLC: t_(R) 2.21 min (Method A); M+H=416, 418 Br-Pattern MS-ES)

Stage 101.1.2 [4-(8-Bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid

To a mixture of [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.3, 3.22 g, 7.73 mmol) and tetrabutylammonium (250 mg, 0.773 mmol) in CH₂Cl₂ (150 ml) was added 1 M aqueous NaOH (80 ml). The reaction mixture was energetically stirred for 4 h30 at rt. The organic layer was separated and the aqueous layer washed with CH₂Cl₂ (2×), adjusted to pH 4 with concentrated aqueous HCl and extracted with n-butanol (5×). The combined organic layers were washed with brine adjusted to pH 4 with HCl and evaporated to dryness. The residue was dry loaded on Isolute, washed with water/1-propanol 3% and eluted with acetonitrile/1-propanol 3% on reverse phase silica gel plug. To acetonitrile filtrate was added water and solution was concentrated. The formed precipitate was filtered, washed with water and dried to give the title compound as a yellow solid. (HPLC: t_(R) 2.08 min (Method A); M+H=402, 404 Br-Pattern MS-ES)

Stage 101.1.3 [4-(8-Bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester

The title compound was synthesized in a similar manner as described in Stage A.1-3 using (4-amino-3-methyl-pyrazol-1-yl)-acetic acid methyl ester (Stage 101.1.4) to give the title compound as green solid. (HPLC: t_(R) 2.35 min (Method A))

Stage 101.1.4 (4-Amino-3-methyl-pyrazol-1-yl)-acetic acid methyl ester

The title compound was synthesized in a similar manner as described in Stage A.2 starting from 3-Methyl-4-nitro-pyrazol-1-yl-acetic acid methylester (ChemCollect, Remscheid, Germany) to give the title compound as a pinkish oil. (HPLC: t_(R) 0.96 min (Method A); M+H=170 MS-ES)

Example 102 2-{4-[8-(6-Methoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N,N-dimethyl-acetamide

A mixture of {4-[8-(6-Methoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-acetic acid TFA salt (Example 101, 60 mg, 0.107 mmol), TPTU (128 mg, 0.430 mmol) and DIPEA (0.094 ml, 0.537 mmol) in DMA (1.5 ml) was stirred under argon at rt for 20 min. Then dimethylamine in THF 2 M (Aldrich, Buchs, Switzerland, 0.242 ml, 0.483 mmol) was added and the RM was stirred at rt for 3 h. The RM was directly purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 50:50). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting layer was extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: t_(R) 2.57 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.50-8.43 (m, 1H), 8.14-8.04 (m, 2H), 8.01-7.96 (m, 1H), 7.95-7.90 (m, 1H), 7-77-7.71 (m, 1H), 6.87-6.81 (m, 1H), 5.25-5.09 (m, 2H), 3.86 (s, 3H), 3.56 (s, 3H), 3.05 (s, 3H), 2.88 (s, 3H), 1.93 (s, 3H))

Example 103.1 1-[1-(2-Hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 103.1.1, 37.4 mg, 0.093 mmol) and 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 20 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.42 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.10-8.05 (m, 1H), 7.95-7.88 (m, 1H), 7.81-7.75 (m, 1H), 7.51-7.46 (m, 1H), 6.93-6.86 (m, 1H), 5.00-4.94 (m, 1H), 4.24-4.17 (m, 2H), 3.88 (s, 3H), 3.86-3.74 (m, 2H), 3.57 (s, 3H), 1.94 (s, 3H))

Stage 103.1.1 8-Bromo-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.1a, 60 mg, 0.139 mmol) and MeOH (0.021 ml, 0.519 mmol) in THF (1.5 ml) was cooled to 0° C. Then NaBH₄ (14 mg, 0.370 mmol) was added and the RM was heated to 50° C. for 30 min. After that, the RM was quenched with saturated aqueous NaHCO₃ (20 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a lightly yellow solid. (HPLC: t_(R) 2.23 min (Method A); M+H=402, 404 Br-Pattern MS-ES)

Alternatively, the title compound was synthesized in a similar manner as described for intermediate A starting from 2-(4-amino-3-methyl-pyrazol-1-yl)-ethanol (Stage 103.1.2).

The following example was synthesized in a similar manner as described for Example 1.1 using 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany) and 8-bromo-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 103.1.1).

HPLC MS-ES t_(R) Example structure Name of the example (M + H) (min) 103.2

8-(6-Ethoxy-pyridin-3- yl)-1-[1-(2-hydroxy- ethyl)-3-methyl-1H- pyrazol-4-yl]-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 445 2.47

Stage 103.1.2 2-(4-Amino-3-methyl-pyrazol-1-yl)-ethanol

To solution of 3-methyl-4-nitropyrazol-1-yl-acetic acid methylester (ChemCollect, Remscheid, Germany, 297 mg, 1.491 mmol) in THF (12 ml) cooled with an ice-bath was added a 1 M solution of lithium aluminium hydride in THF (1.5 ml, 1.5 mmol). The reaction mixture was stirred 1 h at rt then was added more of the reducing reagent (0.75 ml, 0.75 mmol), stirring 2 h at rt, (1.5 ml, 1.5 mmol), stirring 45 min, (2 ml, 2 mmol) and the reaction mixture was stirred 17 h at rt before being quenched with water and taken in EtOAc. The suspension was filtered and the solid washed with EtOAc. The filtrate was dried over Na₂SO₄, filtered and evaporated to give crude brown solid. (HPLC: t_(R) 0.85 min (Method A); M+H=142 MS-ES)

Example 104 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a mixture of 1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 16.1, 28 mg, 0.068 mmol) in DMF (1 ml) was added NaH 55% (4 mg, 0.092 mmol) and the mixture was stirred for 20 min. Then iodomethane (0.006 ml, 0.096 mmol) was added and the RM was stirred again at rt for 30 min. After that, the RM was quenched with saturated aqueous NaHCO₃ (20 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was dissolved in DMA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.30 min (Method A); M+H=429 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 8.15-8.10 (m, 1H), 7.98-7.93 (m, 1H), 7.92-7.87 (m, 1H), 7.58-7.53 (m, 1H), 7.49-7.44 (m, 1H), 4.54-4.50 (m, 2H), 4.23-4.15 (m, 2H), 3.58 (s, 3H), 3.37 (s, 3H), 1.95 (s, 3H), 1.32 (t, 3H))

Example 105 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 104 using 8-(6-hydroxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 16.3, 26 mg, 0.061 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.39 min (Method A); M+H=443 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.68-8.59 (m, 1H), 8.27-8.20 (m, 1H), 8.17-8.09 (m, 1H), 7.99-7.85 (m, 2H), 7.59-7.51 (m, 1H), 7.49-7.41 (m, 1H), 4.60-4.49 (m, 3H), 3.59 (s, 3H), 3.38 (s, 3H), 1.98 (s, 3H), 1.47 (s, 6H))

Example 106 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a mixture of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 106.1.1, 95 mg, 0.195 mmol) in MeOH (2 ml) was added dioxane 4 M (0.248 ml, 0.993 mmol) and the RM was stirred at rt for 45 min. Then the RM was evaporated, before being quenched with saturated aqueous NaHCO₃ (20 ml) and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was diluted with MeOH+2 drops TFA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing product were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: t_(R) 2.24 min (Method A); M+H=404 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.87 (s, 1H), 8.14-8.08 (m, 1H), 8.01-7.92 (m, 2H), 7.82-7.75 (m, 1H), 7.52-7.47 (m, 1H), 7.39-7.35 (m, 1H), 4.96-4.89 (m, 1H), 4.17-4.11 (m, 2H), 3.96 (s, 3H), 3.77-3.69 (m, 2H), 3.55 (s, 3H), 1.94 (s, 3H))

Stage 106.1.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 80 mg, 0.215 mmol) and 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 106.1.2, 91 mg, 0.279 mmol) to give the title compound as red sticky oil. Used for next step without further purification. (HPLC: t_(R) 2.66 min (Method A); M+H=488 MS-ES)

Stage 106.1.2 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

To a solution of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (Stage 106.1.3, 8.50 g, 26.4 mmol) in THF at 0° C. under argon was added dropwise iPrMgCl 2 M in THF (26.4 ml, 52.8 mmol). The RM was stirred at 0° C. for 1 h. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Aldrich, Buchs, Switzerland, 6.25 g, 52.8 mmol) was added at 0° C. and the solution was stirred again and allowed to warm to rt for 1 h. After that, the RM was quenched with saturated aqueous NH₄Cl (140 ml) and extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous NH₄Cl, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (hexane/EtOAc 5% to 45%). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC: t_(R) 3.23 min (Method A); M+H=323 MS-ES)

Stage 106.1.3 4-Iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole

To a mixture of 4-iodopyrazole (Aldrich, Buchs, Switzerland, 10 g, 51.6 mmol) and Cs₂CO₃ (20.16 g 61.9 mmol) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (Aldrich, Buchs, Switzerland, 9.74 ml, 61.9 mmol). The RM was stirred at 70° C. for 17 h. Then the RM was quenched with water (100 ml) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (hexane/EtOAc 0% to 30%). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC: t_(R) 3.12 min (Method A); M+H=323 MS-ES)

Example 107 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a mixture of 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-hydroxy-ethylamino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 19, 40 mg, 0.077 mmol) in MeOH/THF=1:1 (4 ml) was added under nitrogen Pd/C 10% (20 mg, 0.026 mmol). The RM was shacked under H₂ at rt for 22 h. The reaction was not completed, again Pd/C catalyst (20 mg) was added and the mixture was stirred under H₂ at rt for 22 h. This procedure was repeated for a third time. Then the suspension was filtered over celite and washed with MeOH. The filtrate was evaporated. The residue was dissolved in MeOH and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing product were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.32 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.30-8.26 (m, 1H), 8.17-8.06 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.75 (m, 1H), 7.50-7.46 (m, 1H), 6.97-6.91 (m, 1H), 4.80-4.86 (m, 1H), 4.34-4.28 (m, 2H), 3.92 (s, 3H), 3.75-3.69 (m, 2H), 3.58 (s, 3H), 1.95 (s, 3H))

Example 108 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(3-hydroxy-propoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 107 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-[6-(2-hydroxy-ethylamino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 20, 42 mg, 0.078 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.42 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.33-8.25 (m, 1H), 8.18-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.80-7.73 (m, 1H), 7.51-7.45 (m, 1H), 6.97-6.89 (m, 1H), 4.57-4.50 (m, 1H), 4.41-4.31 (m, 2H), 3.93 (s, 3H), 3.61-3.52 (m, 5H), 1.97 (s, 3H), 1.91-1.82 (m, 2H))

Example 109 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 49 mg, 0.137 mmol), 2-methoxypyridine-5-boronic acid (Sigma-Aldrich, Buchs, Switzerland, 26 mg, 0.170 mmol), and PdCl₂(PPh₃)₂ (6 mg, 0.0085 mmol) in DMF (1.2 ml) and 1 M aqueous K₂CO₃ (0.343 ml) was stirred under argon at 105° C. for 1.5 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.46 min (Method A); M+H=387 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.66 (s, br, 1H), 8.72 (s, 1H), 8.33-8.26 (m, 1H), 8.16-8.10 (m, 1H), 8.09-8.01 (m, 1H), 7.91-7.84 (m, 1H), 7.81-7.74 (m, 1H), 7.51-7.43 (m, 1H), 6.98-6.91 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 1.95 (s, 3H))

Example 110 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethoxy-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 109 using 2-ethoxypyridine-5-boronic acid (ABCR, Karlsruhe, Germany, 29 mg, 0.170 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.59 min (Method A); M+H=401 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.67 (s, br, 1H), 8.71 (s, 1H), 8.30-8.25 (m, 1H), 8.15-8.11 (m, 1H), 8.07-8.02 (m, 1H), 7.90-7.84 (m, 1H), 7.79-7.73 (m, 1H), 7.49-7.44 (m, 1H), 6.95-6.88 (m, 1H), 4.33 (q, 2H), 3.89 (s, 3H), 1.95 (s, 3H), 1.33 (t, 3H))

Example 111 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 109 using (3,4-dimethoxyphenyl)boronic acid (Aldrich, Buchs, Switzerland, 31 mg, 0.167 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.57 min (Method A); M+H=416 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.67 (s, br, 1H), 8.68 (s, 1H), 8.14-8.09 (m, 1H), 8.05-7.98 (m, 1H), 7.94-7.87 (m, 1H), 7.56-7.51 (m, 1H), 7.12-7.07 (m, 1H), 7.07-7.00 (m, 1H), 6.97-6.92 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 1.97 (s, 3H))

Example 112 5-[1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid amide

A mixture of 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 112.1.1, 34 mg, 0.075 mmol), 5-bromo-pyridine-2-carboxylic acid amide (Combi-Blocks, San Diego, USA, 20 mg, 0.099 mmol), and PdCl₂(PPh₃)₂ (3.5 mg, 0.005 mmol) in DMF (0.9 ml) and 1 M aqueous K₂CO₃ (0.187 ml) was stirred under argon at 105° C. for 2.5 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 97:3 to 55:45). The fractions containing product were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: t_(R) 2.44 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.75-8.69 (m, 1H), 8.24-8.19 (m, 1H), 8.18-8.07 (m, 2H), 8.07-7.98 (m, 3H), 7.75-7.67 (m, 1H), 7.61-7.56 (m, 1H), 4.61-4.48 (m, 1H), 3.58 (s, 3H), 1.97 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H))

Stage 112.1.1 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 100 mg, 0.250 mmol), bis(pinacolato)-diborane (Aldrich, Buchs, Switzerland, 78 mg, 0.3 mmol), potassium acetate (74 mg, 0.754 mmol) and PdCl₂(dppf) (8 mg, 0.011 mmol) in dioxane (1.1 ml) and DMSO (0.02 ml) was stirred in a closed microwave vial flushed with argon at 90° C. for 7.5 h. Then the RM was diluted with EtOAc and washed with brine (2×). The organic layer was dried over Na₂SO₄, filtered and evaporated to dryness. The residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH 0% to 4%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: t_(R) 2.16 min (Method A); M+H=448 MS-ES)

Example 113 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-2-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described in Example 112 using 2-bromopyridine (Aldrich, Buchs, Switzerland, 0.009 ml, 0.093 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.49 min (Method A); M+H=399 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.61-8.56 (m, 1H), 8.28-8.23 (m, 1H), 8.23-8.19 (m, 1H), 8.13-8.06 (m, 2H), 7.88-7.81 (m, 1H), 7.69-7.63 (m, 1H), 7.38-7.31 (m, 1H), 4.63-4.52 (m, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.51 (d, 6H))

Example 114 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-2-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described in Example 112 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 114.1.1, 34.5 mg, 0.082 mmol) and 2-bromopyridine (Aldrich, Buchs, Switzerland, 0.011 ml, 0.114 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.25 min (Method A); M+H=371 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.67-8.61 (m, 1H), 8.30-8.24 (m, 1H), 8.17-8.06 (m, 3H), 7.94-7.86 (m, 1H), 7.67-7.61 (m, 1H), 7.39-7.32 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H))

Stage 114.1.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described in stage 112.1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 200 mg, 0.532 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.00 min (Method A); M+H=420 MS-ES)

Example 115 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyrazin-2-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described in Example 112 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 114.1.1, 33.5 mg, 0.080 mmol) and 2-bromopyrazine (Synchem, Huddersfield, UK, 17.2 mg, 0.108 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.34 min (Method A); M+H=372 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.98 (s, 1H), 8.72-8.70 (m, 1H), 8.62-8.60 (m, 1H), 8.32-8.28 (m, 1H), 8.16-8.13 (m, 3H), 3.94 (s, 3H), 3.59 (s, 3H), 1.95 (s, 3H))

Example 116 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 36, 45.4 mg, 0.111 mmol) in 1.5 ml anhydrous DMF was treated with 55% NaH in oil (6.0 mg, 0.138 mmol). The reaction mixture was stirred for 20 min at rt, then was added iodomethane (0.009 ml, 138 mmol). The reaction mixture was stirred for 1.5 h at rt. The RM was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.62 min (Method A); M+H=424 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.38-8.36 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.09 (m, 1H), 8.06-8.04 (m, 1H), 7.99-7.95 (m, 1H), 7.60-7.58 (m, 1H), 7.57-7.55 (m, 1H), 6.54-6.51 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Example 117 N-{3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-phenyl}-N-methyl-methanesulfonamide

The title compound was synthesized in a similar manner as described for Stage 62.1.2 using N-{3-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-phenyl}-methanesulfonamide (Example 47) to give the title compound as a white solid. (HPLC: t_(R) 2.59 min (Method A); M+H=477 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.16-8.07 (m, 2H), 7.95-7.90 (m, 1H), 7.60-7.56 (m, 1H), 7.54-7.48 (m, 1H), 7.47-7.40 (m, 3H), 3.90 (s, 3H), 3.57 (s, 3H), 3.29 (s, 3H), 2.99 (s, 3H), 1.95 (s, 3H))

Example 118.1 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 58.8 mg, 0.147 mmol) and 6-(N-boc-methylamino)pyridine-3-boronic acid pinacol ester (Alfa Aesar, Heysham, UK, 58.8 mg, 0.176 mmol) to give crude boc-protected title compound that is treated for 25 min at rt with trifluoroacetic acid (1.5 ml) and then purified by prep. HPLC to give the title compound as a light yellow solid. (HPLC: t_(R) 2.21 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.23-8.14 (m, 2H), 8.05-7.98 (m, 1H), 7.87-7.79 (m, 1H), 7.48-7.37 (m, 2H), 6.78-6.70 (m, 1H), 6.49-6.42 (m, 1H), 4.61-4.50 (m, 1H), 3.56 (s, 3H), 2.77 (d, 3H), 1.95 (d, 3H), 1.51-1.45 (m, 6H))

The following examples were synthesized in a similar manner as described for Example 118 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 118.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-3- methyl-8-(6- methylamino-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 400 2.09 118.3 L

N,N-Dimethyl-2-{3- methyl-4-[3-methyl-8- (6-methylamino- pyridin-3-yl)-2-oxo- 2,3-dihydro- imidazo[4,5- c]quinolin-1-yl]- pyrazol-1-yl}- acetamide 471 2.09 118.4 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-8-(6- methylamino-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 414 2.07 118.5 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-3- methyl-8-(6- methylamino-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 420 2.18

Example 119 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methyl-6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 6-(N-boc-methylamino)-5-methylpyridine-3-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 58.8 mg, 0.176 mmol) to give crude boc-protected title compound that was treated for 30 min at rt with trifluoroacetic acid (0.5 ml) and then purified by prep. HPLC to give the title compound as an off-white foam. (HPLC: t_(R) 2.24 min (Method A); M+H=434 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.40 (s, 1H), 8.14-8.12 (m, 1H), 8.05-8.03 (m, 1H), 7.90-7.85 (m, 1H), 7.38-7.37 (m, 2H), 6.28-6.20 (br, 1H), 4.01 (s, 3H), 3.58 (s, 3H), 2.88 (m, 3H), 2.11 (s, 3H))

Example 120 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-methanesulfonamide

The title compound was synthesized in a similar manner as described for Stage 75.1.3 using 8-(5-amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 45, 72 mg, 0.187 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.19 min (Method A); M+H=464 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 10.20-10.15 (m, 1H), 9.00 (s, 1H), 8.43-8.37 (m, 2H), 8.19-8.09 (m, 2H), 7.92-7.84 (m, 1H), 7.72-7.66 (m, 1H), 7.61-7.56 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.11 (s, 3H), 1.96 (s, 3H))

Example 121 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-N-methyl-methanesulfonamide

The title compound was synthesized in a similar manner as described for stage 62.1.2 using N-{5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-methanesulfonamide (Example 120) to give the title compound as an off-white solid. (HPLC: t_(R) 2.28 min (Method A); M+H=478 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.64-8.58 (m, 2H), 8.17-8.12 (m, 2H), 8.03-7.97 (m, 1H), 7.92-7.88 (m, 1H), 7.63-7.59 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.35 (s, 3H), 3.07 (s, 3H), 1.96 (s, 3H))

Example 122 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of 8-(5-amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 45, 38 mg, 0.099 mmol), acetaldehyde (Fluka, Buchs, Switzerland, 4.8 mg, 0.108 mmol) in DCM (2 ml) was stirred for 1.5 h at rt in presence of acetic acid (0.02 ml, 3.54 mmol). Was added sodium triacetoxyborohydride (52.2 mg, 0.246 mmol) and the RM was stirred 1.5 h at rt, before being quenched with aqueous saturated NaHCO₃ and extracted with DCM (2×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to dryness. The residue was purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 60:40). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated, saturated with NaCl and extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to give the title compound as an off-white solid. (HPLC: t_(R) 2.13 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.08 (m, 2H), 7.97-7.95 (m, 1H), 7.92-7.88 (m, 2H), 7.60-7.58 (m, 1H), 6.88-6.85 (m, 1H), 6.01 (t, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.15-3.06 (m, 2H), 1.95 (s, 3H), 1.21 (t, 3H))

Example 123 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(2H-tetrazol-5-yl)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of 5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carbonitrile (stage 123.1.1, 41.1 mg, 0.104 mmol), sodium azide (10 mg, 0.154 mmol) and ammonium chloride (18 mg, 0.337 mmol) in DMF (0.3 ml) was sealed and heated at 120° C. for 80 min. The reaction mixture was quenched with aqueous NaHCO₃ and washed with EtOAc (2×). The aqueous layer was adjusted to pH 5 with 1 M aqueous HCl and extracted with dichloromethane (3×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated. The crude product was purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing products were collected together and lyophilized to give the title compound as a white lyophilizate TFA salt. (HPLC: t_(R) 2.34 min (Method A); M+H=439 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.18 (s, 1H), 8.90-8.85 (m, 1H), 8.37-8.32 (m, 1H), 8.26-8.15 (m, 4H), 7.75-7.70 (m, 1H), 3.94 (s, 3H), 3.61 (s, 3H), 2.00 (s, 3H))

Stage 123.1.1 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carbonitrile

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-cyanopyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a brown solid. (HPLC: t_(R) 2.42 min (Method A); M+H=396 MS-ES)

Example 124 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methoxy-3-(carbomethoxy)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white lyophilizate TFA salt. (HPLC: t_(R) 2.31 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.21 (s, br, 1H), 8.62-8.56 (m, 1H), 8.23-8.16 (m, 3H), 8.11-8.07 (m, 1H), 7.62-7.57 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.59 (s, 3H), 1.94 (s, 3H))

Example 125.1 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-N-methyl-nicotinamide

To a cooled with an ice-bath suspension of 5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid TFA salt (Example 124, 60 mg, 0.089 mmol) in dichloromethane (1.5 ml) containing DMF (0.005 ml) was added oxallyl chloride (0.038 ml, 0.449 mmol). The reaction mixture was stirred for 1 h at rt then cooled with an ice-bath and quenched with 8 M methylamine in ethanol (2.5 ml, 20 mmol). After 5 min stirring, the reaction mixture was evaporated to dryness and the residue purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing products were collected together, basified with NaHCO₃, concentrated and the formed precipitate was filtered, washed with water and dried to give the title compound as white solid. (HPLC: t_(R) 2.45 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.52-8.46 (m, 1H), 8.35-8.27 (m, 1H), 8.19-8.07 (m, 3H), 7.99-7.93 (m, 1H), 7.56-7.51 (m, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.57 (s, 3H), 2.83 (d, 3H), 1.94 (s, 3H))

The following example was synthesized in a similar manner as described for Example 125.1 using ammonia.

HPLC MS-ES t_(R) Example structure Name of the example (M + H) (min) 125.2

5-[1-(1,3-Dimethyl-1H- pyrazol-4-yl)-3- methyl-2-oxo-2,3- dihydro-1H- imidazo[4,5- c]quinolin-8-yl]-2- methoxy-nicotinamide 444 2.35

Example 126 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-piperazin-1-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 118.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-(4-boc-piperazine)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: t_(R) 1.97 min (Method A); M+H=455 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.30-8.25 (m, 1H), 8.14-8.11 (m, 1H), 8.07-8.01 (m, 1H), 7.90-7.84 (m, 1H), 7.62-7.56 (m, 1H), 7.46-7.41 (m, 1H), 6.95-6.89 (m, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 3.53-3.46 (m, 4H), 2.86-2.76 (m, 4H), 1.95 (s, 3H))

Example 127 8-(5-Amino-6-methoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 66, 50 mg, 0.112 mmol) in 5 ml THF and 5 ml MeOH was stirred in presence of palladium 10% on charcoal under 1.1 bar of hydrogen for 5 h at rt. The reaction mixture was filtered over Celite and the catalyst was washed with MeOH/THF. The filtrate was evaporated and the crude product was purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 50:50). The fractions containing products were collected together, basified with NaHCO₃, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to give the title compound as a light yellow solid. (HPLC: t_(R) 2.29 min (Method A); M+H=416 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.94 (s, 1H), 8.12-8.10 (m, 1H), 8.08-8.05 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.45 (m, 1H), 7.43-7.41 (m, 1H), 7.00-6.97 (m, 1H), 5.11 (s, br, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H))

Example 128.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinoline-2-thione

A mixture of a new batch of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 10.2, 8 mg, 0.219 mmol) and Lawesson's reagent (98 mg, 0.242 mmol) in dioxane (1 ml) was stirred in a seal vial for 28 h at 100° C. The reaction mixture was quenched with saturated aqueous NaHCO₃ and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness. The residue was taken in NMP and purified by Prep.HPLC (H₂O (0.1% TFA)/CH₃CN 95:5 to 65:35). The fractions containing products were collected together and basified with NaHCO₃ (0.3 g), before being concentrated. The resulting suspension was filtered and the cake was washed with water, before being dried under high vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.32 min (Method A); M+H=387 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.21 (s, 1H), 8.72-8.68 (m, 1H), 8.62-8.58 (m, 1H), 8.23-8.16 (m, 2H), 8.08-8.04 (m, 1H), 7.93-7.88 (m, 1H), 7.56-7.48 (m, 2H), 3.97-3.93 (m, 6H), 1.92 (s, 3H))

The following example was synthesized in a similar manner as described for Example 128.1 using Example 1.8 as starting material.

HPLC MS-ES t_(R) Example structure Name of the example (M + H) (min) 128.2

8-(3,4-Dimethoxy- phenyl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinoline-2-thione 446 2.85

Example 129 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 116 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 99) to give the title compound as an off-white solid. (HPLC: t_(R) 2.11 min (Method A); M+H=424 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.47-8.45 (m, 1H), 8.18-8.16 (m, 1H), 8.15-8.11 (m, 1H), 8.08-8.04 (m, 1H), 8.00-7.98 (m, 1H), 7.71-7.69 (m, 1H), 7.65-7.63 (m, 1H), 6.59-6.57 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))

Example 130 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[2-(isopropyl-methyl-amino)-pyridin-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and isopropyl-methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 130.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.24 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.14-8.08 (m, 3H), 7.97-7.93 (m, 1H), 7.69-7.66 (m, 1H), 6.69-6.66 (m, 1H), 6.56-6.53 (m, 1H), 4.90 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.85 (s, 3H), 1.96 (s, 3H), 1.17-1.11 (m, 6H))

Stage 130.1.1 Isopropyl-methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine

The title compound was synthesized in a similar manner as described for stage 5.1.1-2 using 4-bromo-2-chloropyridine (Aldrich, Buchs, Switzerland) and N-methylisopropylamine (Aldrich, Buchs, Switzerland) to give the title compound as a brown oil. (HPLC: t_(R) 2.06 min (Method A); M+H=277 MS-ES).

Example 131 8-(6-Ethoxy-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 104 using 8-(6-ethoxy-pyridin-3-yl)-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 103.2) to give the title compound as an off-white solid. (HPLC: t_(R) 2.70 min (Method A); M+H=459 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.28-8.26 (m, 1H), 8.12-8.06 (m, 2H), 7.91-7.87 (m, 1H), 7.81-7.78 (m, 1H), 7.49-7.47 (m, 1H), 6.90-6.87 (m, 1H), 4.37-4.29 (m, 4H), 3.71 (q, 2H), 3.58 (s, 3H), 3.12 (s, 3H), 1.97 (s, 3H), 1.33 (t, 3H))

Example 132 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinonitrile

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.60 min (Method A); M+H=426 MS-ES)

Example 133 8-(6-Ethoxy-pyridin-3-yl)-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 133.1.1) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany) to give the title compound as a white solid. (HPLC: t_(R) 2.27 min (Method A); M+H=527 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.69 (s, br, 1H), 8.71 (s, 1H), 8.45-8.42 (m, 1H), 8.08-8.03 (m, 2H), 7.96-7.88 (m, 2H), 7.74-7.71 (m, 1H), 6.81-6.67 (m, 1H), 5.27-5.11 (m, 2H), 4.32 (q, 2H), 3.58-3.38 (m, 4H), 2.38-2.26 (m, 4H), 2.19 (s, 3H), 1.92 (s, 3H), 1.31 (t, 2H))

Stage 133.1. 8-Bromo-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.2, 178 mg, 0.443 mmol), DIPE (0.232 ml, 1.33 mmol), TPTU (223 mg, 0.752 mmol) in DMA (5 ml) was stirred at rt for 5 min, then was added N-methylpiperazine (0.1 ml, 0.90 mmol). The reaction mixture was stirred 19 h at rt and then was added N-methylpiperazine (0.1 ml, 0.90 mmol) and the reaction mixture was stirred 25 h at rt. The reaction mixture was purified by prep. HPLC to give the title compound as an off-white solid. (HPLC: t_(R) 1.98 min (Method A); M+H=484, 486 MS-ES)

Example 134 3-Methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-8-phenyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 134.1.1) and phenylboronic acid (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 2.32 min (Method A); M+H=496 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.96-7.92 (m, 1H), 7.81-7.79 (m, 1H), 7.69-7.65 (m, 2H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 5.28-5.16 (m, 2H), 3.59-3.43 (m, 7H), 2.40-2.29 (m, 4H), 2.20 (s, 3H), 1.92 (s, 3H))

Stage 134.1 8-Bromo-3-methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Intermediate A using 8-bromo-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 133.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.06 min (Method A); M+H=498, 500 MS-ES)

Example 135 N-Ethyl-N-methyl-2-[3-methyl-4-(3-methyl-2-oxo-8-phenyl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-pyrazol-1-yl]-acetamide

The title compound was synthesized in a similar manner as described for Example 134 using N-ethyl-N-methylamine (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 2.76 min (Method A); M+H=455 MS-ES; ¹H-NMR (d₆-DMSO, 500 MHz) 8.98 (s, 1H), 8.14-8.09 (m, 2H), 7.98-7.94 (m, 1H), 7.83-7.81 (m, 1H), 7.72-7.68 (m, 2H), 7.47-7.42 (m, 2H), 7.38-7.34 (m, 1H), 5.25-5.15 (m, 2H), 3.60 (s, 3H), 3.48-3.36 (m, 2H), 3.05 and 2.90 (2×s, 3H), 1.93 and 1.93 (2×s, 3H), 1.20 and 1.08 (2×t, 3H))

Example 136 2-{4-[8-(6-Ethoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N-ethyl-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Example 135 using 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany) to give the title compound as a white solid. (HPLC: t_(R) 2.70 min (Method A); M+H=500 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.46-8.43 (m, 1H), 8.11-8.05 (m, 2H), 8.00-7.91 (m, 2H), 7.74-7.71 (m, 1H), 6.77-6.82 (m, 1H), 5.24-5.10 (m, 2H), 4.36-4.28 (m, 2H), 3.57 (s, 3H), 3.46-3.30 (m, 2H), 3.02 and 2.86 (2×s, 3H), 1.92 and 1.91 (2×s, 3H), 1.31 (t, 3H), 1.18 and 1.03 (2×t, 3H))

Example 137 N-(2-Methoxy-ethyl)-N-methyl-2-[3-methyl-4-(3-methyl-2-oxo-8-phenyl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-pyrazol-1-yl]-acetamide

The title compound was synthesized in a similar manner as described for Example 134 using N-(2-methoxyethyl)-N-methylamine (ABCR, Karlsruhe, Germany) to give the title compound as a white foam. (HPLC: t_(R) 2.73 min (Method A); M+H=485 MS-ES; ¹H-NMR (d₆-DMSO, 500 MHz) 8.96 (s, 1H), 8.12-8.07 (m, 2H), 7.97-7.93 (m, 1H), 7.82-7.79 (m, 1H), 7.70-7.65 (m, 2H), 7.45-7.40 (m, 2H), 7.38-7.32 (m, 1H), 5.28-5.15 (m, 2H), 3.62-3.44 (m, 7H), 3.33 and 3.26 (2×s, 3H), 3.09 and 2.93 (2×s, 3H), 1.92 and 1.91 (2×s, 3H))

Example 138 1-[1-(2-Azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(6-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 134 using azetidine (Fluka, Buchs, Switzerland) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany) to give the title compound as a white solid. (HPLC: t_(R) 2.62 min (Method A); M+H=498 MS-ES; ¹H-NMR (d₆-DMSO, 500 MHz) 8.95 (s, 1H), 8.41-8.39 (m, 1H), 8.13-8.07 (m, 2H), 7.95-7.88 (m, 2H), 7.61-7.63 (m, 1H), 6.86-6.82 (m, 1H), 4.94-4.84 (m, 2H), 4.34 (q, 2H), 4.27-4.15 (m, 2H), 3.99-3.88 (m, 2H), 3.58 (s, 3H), 2.28-2.14 (m, 2H), 1.94 (s, 3H), 1.33 (t, 3H))

Example 139 N,N-Diethyl-2-{3-methyl-4-[3-methyl-8-(6-methyl-pyridin-3-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide

The title compound was synthesized in a similar manner as described for Example 134 using dimethylamine (Fluka, Buchs, Switzerland) and 2-methylpyridine-5-boronic acid (Frontier Scientific, Logan, USA) to give the title compound as a white foam. (HPLC: t_(R) 2.21 min (Method A); M+H=484 MS-ES; ¹H-NMR (d₆-DMSO, 500 MHz) 8.97 (s, 1H), 8.71-8.69 (m, 1H), 8.13-8.08 (m, 2H), 7.97-7.92 (m, 2H), 7.80-7.78 (m, 1H), 7.28-7.25 (m, 1H), 5.21-5.09 (m, 2H), 3.59 (s, 3H), 3.44-3.28 (m, 7H), 1.93 (s, 3H), 1.20 (t, 3H), 1.05 (t, 3H))

Example 140.1 N-Ethyl-N-methyl-2-{3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-N-ethyl-N-methyl-acetamide (Intermediate P) and 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 37 mg, 0.132 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.53 min (Method A); M+H=526 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) cis&trans amide 8.92 (s, 1H), 8.59-8.55 (m, 2H), 8.08-8.01 (m, 2H), 7.88-7.84 (m, 1H), 7.68-7.63 (m, 1H), 5.23-5.15 (m, 1H), 5.11-5.04 (m, 1H), 3.57 (s, 3H), 3.53-3.21 (m, 6H), 3.01, 2.83 (2×s, 3H), 1.97-1.89 (m, 4H), 1.94, 1.93 (2×s, 3H), 1.17, 0.99 (2×t, 3H))

The following example was synthesized in a similar manner as described for Example 1.1 using 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 140.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-3- methyl-8-(2- pyrrolidin-1-yl- pyrimidin-5-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 441 2.44

Example 141.1 8-(5-Fluoro-6-methylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H) and [3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 141.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.15 min (Method A); M+H=432 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.05-7.99 (m, 2H), 7.89-7.84 (m, 1H), 7.41-7.36 (m, 1H), 7.35-7.33 (m, 1H), 6.92-6.86 (m, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 2.88 (d, 3H), 2.07 (s, 3H), 1.91 (s, 3H))

Stage 141.1.1 [3-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine

A mixture of (5-bromo-3-fluoro-pyridin-2-yl)-methyl-amine (Stage 141.1.2, 1.255 mmol), bis(pinacolato)-diborane (1.381 mmol), potassium acetate (3.77 mmol) and PdCl₂(dppf) (0.063 mmol) in dioxane (7 ml) was stirred in a closed vial flushed with argon at 90° C. for 15 h. Then the RM was diluted with toluene (7 ml), sonicated and filtered. The solid residue is washed with hot toluene and the filtrated is evaporated to dryness to give the crude title product as a brown oil. (HPLC: t_(R) 3.68 min (Method A); M+H=253 MS-ES)

Stage 141.1.2 (5-Bromo-3-fluoro-pyridin-2-yl)-methyl-amine

A mixture of 5-bromo-2,3-difluoropyridine (Matrix, Columbia, USA, 2.53 mmol) and 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 2 ml, 16 mmol) was sealed in a vial and heated with microwave irradiation at 100° C. for 30 min. The cooled RM was diluted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title product as an off-white solid. (HPLC: t_(R) 1.94 min (Method A); M+H=205, 207, M−H=203, 205 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using [3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 141.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 141.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-(5- fluoro-6-methylamino- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 418 2.09 141.3 G

8-(5-Fluoro-6- methylamino-pyridin- 3-yl)-1-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 446 2.25

Example 142.1 8-(6-Amino-5-fluoro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H) and 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (stage 142.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.07 min (Method A); M+H=418 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.05-8.01 (m, 1H), 7.91-7.84 (m, 2H), 7.47-7.42 (m, 1H), 7.35-7.32 (m, 1H), 6.49 (s, 2H), 3.83 (s, 3H), 3.58 (s, 3H), 2.07 (s, 3H), 1.90 (s, 3H))

Stage 142.1.1 3-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine

The title compound was synthesized in a similar manner as described for stage 141.1.1-2 using 2 M ammonia in isopropanol (Aldrich, Buchs, Switzerland) and heating up to 195° C. (unstable in the HPLC condition (Method A); M+H=239 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (stage 142.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 142.2 A

8-(6-Amino-5-fluoro- pyridin-3-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 404 2.02 142.3 G

8-(6-Amino-5-fluoro- pyridin-3-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 432 2.17

Example 143 3-Methyl-8-(6-trideuteromethylamino-5-trifluoromethyl-pyridin-3-yl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.104 mmol) and trideuteromethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-yl]-amine (stage 143.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.53 min (Method A); M+H=485 MS-ES; ¹H-NMR (de-DMSO, 400 MHz) 8.94 (s, 1H), 8.51-8.49 (m, 1H), 8.08-8.04 (m, 1H), 7.96-7.92 (m, 1H), 7.72-7.69 (m, 1H), 7.39-7.36 (m, 1H), 6.74 (s, br, 1H), 3.80 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.89 (s, 3H))

Stage 143.1.1 Trideuteromethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-yl]-amine

The title compound was synthesized in a similar manner as described for stage 5.1.1 using (5-bromo-3-trifluoromethyl-pyridin-2-yl)-trideuteromethyl-amine (Stage 143.1.2, 0.833 mmol) to give the title compound as a crude brown oil. (degrading under the HPLC condition (Method A); M+H=306 MS-ES)

Stage 143.1.2 (5-Bromo-3-trifluoromethyl-pyridin-2-yl)-trideuteromethyl-amine

To a solution of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (Stage 25.1.2, 1.66 mmol) in DMF cooled with an ice-bath was added 55% sodium hydride in oil (1.66 mmol). The RM was stirred for 30 min at 0° C. then was added d₃-iodomethane (Aldrich, Buchs, Switzerland, 1.66 mmol) and the RM was stirred for 30 min at rt and the formed slurry was sonicated for 30 min at rt. The RM was quenched with saturated aqueous NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with saturated aqueous NaHCO₃ (3×), with brine, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (hexane/CH₂Cl₂ 1:1 to 1:8) to give the title compound as an oil (HPLC: t_(R) 3.30 min (Method A); M+H=258, 260 MS-ES)

Example 144.1 3-Methyl-8-(6-methylamino-5-trifluoromethyl-pyridin-3-yl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 143 using iodomethane as replacement for d₃-iodomethane to give the title compound as a yellow film. (HPLC: t_(R) 2.53 min (Method A); M+H=482 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.94 (s, 1H), 8.51-8.49 (m, 1H), 8.08-8.04 (m, 1H), 7.96-7.92 (m, 1H), 7.72-7.69 (m, 1H), 7.38-7.36 (m, 1H), 6.77 (q, 1H), 3.79 (s, 3H), 3.58 (s, 3H), 2.92 (d, 3H), 2.07 (s, 3H), 1.89 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 144.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 144.2 G

1-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-8-(6- methylamino-5- trifluoromethyl-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 496 2.73 144.3 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-3- methyl-8-(6- methylamino-5- trifluoromethyl-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 468 2.47

Example 145.1 8-(6-Ethylamino-5-trifluoromethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 143 using iodoethane as replacement for d₃-iodomethane to give the title compound as a yellow foam. (HPLC: t_(R) 2.74 min (Method A); M+H=496 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.94 (s, 1H), 8.50-8.47 (m, 1H), 8.08-8.03 (m, 1H), 7.96-7.91 (m, 1H), 7.71-7.67 (m, 1H), 7.37-7.34 (m, 1H), 6.74 (t, 1H), 3.79 (s, 3H), 3.58 (s, 3H), 3.49 (qt, 2H), 2.08 (s, 3H), 1.89 (s, 3H), 1.14 (t, 3H))

The following example was synthesized in a similar manner as described for Example 145.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 145.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-(6- ethylamino-5- trifluoromethyl-pyridin- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 482 2.70

Example 146.1 8-(5-Chloro-6-methylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.107 mmol) and [3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 146.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.53 min (Method A); M+H=485 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.24-8.21 (m, 1H), 8.15 (s, 1H), 8.06-8.01 (m, 1H), 7.92-7.87 (m, 1H), 7.62-7.57 (m, 1H), 7.40-7.37 (m, 1H), 6.81-6.76 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 2.89 (d, 3H), 1.95 (s, 3H))

Stage 146.1.1 [3-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine

The title compound was synthesized in a similar manner as described for Stage 141.1-2 using 5-bromo-2,3-dichloropyridine (Asymchem Laboratories, Morrisville, N.C., USA) and heating to 150° C. as replacement for 5-bromo-2,3-difluoropyridine to give the title compound as a crude brown oil. (HPLC: t_(R) 1.62 min (Method A); M+H=269 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using [3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 146.2 F

8-(5-Chloro-6- methylamino-pyridin- 3-yl)-1-(1-ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 448 2.30 146.3 G

8-(5-Chloro-6- methylamino-pyridin- 3-yl)-1-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 462 2.40 146.4 H

8-(5-Chloro-6- methylamino-pyridin- 3-yl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 448 2.27 146.5 C

8-(5-Chloro-6- methylamino-pyridin- 3-yl)-1-(2,5-dimethyl- 2H-pyrazol-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 434 2.39 146.6 Q

8-(5-Chloro-6- methylamino-pyridin- 3-yl)-1-(3,5-dimethyl- isoxazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 435 2.35

Example 147 8-(5-Chloro-6-ethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 146.1 using 2 Methylamine in MeOH (Aldrich, Buchs, Switzerland) as replacement for the methylamine to give the title compound as a beige foam. (HPLC: t_(R) 2.35 min (Method A); M+H=448 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.22-8.20 (m, 1H), 8.16 (s, 1H), 8.05-8.01 (m, 1H), 7.91-7.87 (m, 1H), 7.61-7.58 (m, 1H), 7.39-7.36 (m, 1H), 6.74 (t, 1H), 3.94 (s, 3H), 3.57 (s, 3H), 3.43 (qt, 2H), 1.94 (s, 3H), 1.15 (t, 3H))

Example 148 8-(6-Amino-5-chloro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.075 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (stage 148.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.53 min (Method A); M+H=485 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.94 (s, 1H), 8.51-8.49 (m, 1H), 8.08-8.04 (m, 1H), 7.96-7.92 (m, 1H), 7.72-7.69 (m, 1H), 7.39-7.36 (m, 1H), 6.74 (s, br, 2H), 3.80 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.89 (s, 3H))

Stage 148.1.1 3-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-amino-5-bromo-3-chloropyridine (Beta Pharma, New Haven, Conn., USA) to give the title compound as a crude sticky black solid. (degrading under the HPLC condition: t_(R) 1.44 min (Method A); M+H=255 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 148.2 A

8-(6-Amino-5-chloro- pyridin-3-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 420 2.14 148.3 F

8-(6-Amino-5-chloro- pyridin-3-yl)-1-(1- ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 434 2.21 148.4 Q

8-(6-Amino-5-chloro- pyridin-3-yl)-1-(3,5- dimethyl-isoxazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 421 2.24

Example 149 8-(5-Amino-6-fluoro-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (stage 149.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.53 min (Method A); M+H=485 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.20 (s, 1H), 8.12-8.08 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.44 (m, 1H), 7.29-7.23 (m, 2H), 5.57 (s, br, 2H), 4.54 (hp, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.44 (d, 6H))

Stage 149.1.1 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 3-amino-5-bromo-2-fluoropyridine (Matrix Scientific, Columbia, S.C., USA) to give the title compound as a crude sticky black solid. (degrading under the HPLC condition (Method A); M+H=239 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 149.2 A

8-(5-Amino-6-fluoro- pyridin-3-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 404 2.27 149.3 C

8-(5-Amino-6-fluoro- pyridin-3-yl)-1-(2,5- dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 404 2.21

Example 150.1 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-fluoro-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.078 mmol) and [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methyl-amine (stage 150.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.53 min (Method A); M+H=485 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.16 (s, 1H), 8.11-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.53-7.51 (m, 1H), 7.42-7.39 (m, 1H), 7.01-6.97 (m, 1H), 6.08 (q, br, 1H), 4.15 (q, 2H), 3.58 (s, 3H), 2.80 (d, 3H), 1.97 (s, 3H), 1.37 (t, 3H))

Stage 150.1.1 [2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methyl-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-fluoro-3-methylaminopyridine (Stage 150.1.2) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.70 min (Method A); M+H=239 MS-ES).

Stage 150.1.2 (5-Bromo-2-fluoro-pyridin-3-yl)-methyl-amine

A mixture of 3-amino-5-bromo-2-fluoropyridine (Matrix Scientific, Columbia, S.C., USA, 1.571 mmol) in DMF (3 ml) and 55% NaH in oil (1.571 mmol) was stirred for 15 min at rt. Was added iodomethane (Aldrich, Buchs, Switzerland, 1.571 mmol) and the RM was stirred for 13 h at rt. The RM was diluted with EtOAc, washed with brine (4×), dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fraction containing the first eluting product were evaporated to give (5-bromo-2-fluoro-pyridin-3-yl)-dimethyl-amine as an orange oil (HPLC: t_(R) 3.15 min (Method A); M+H=219, 221 MS-ES) and the fraction containing the second eluting product were evaporated to give the title compound as a red solid (HPLC: t_(R) 2.90 min (Method A); M+H=205, 207 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methyl-amine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 150.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-(6- fluoro-5-methylamino- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 418 2.45

Example 151 8-(5-Dimethylamino-6-fluoro-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and [2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-dimethyl-amine (stage 151.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.59 min (Method A); M+H=432 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.13-8.08 (m, 2H), 7.99-7.94 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.54 (m, 1H), 7.28-7.23 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.89 (s, 6H), 1.96 (s, 3H))

Stage 151.1.1 [2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-dimethyl-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-fluoro-3-dimethylaminopyridine (Stage 150.1.2, side product) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.77 min (Method A); M+H=267 MS-ES).

Example 152.1 8-(5-Amino-6-chloro-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (stage 152.1.1) to give the title compound as a yellow foam. (HPLC: t_(R) 2.55 min (Method A); M+H=448 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.19 (s, 1H), 8.14-8.09 (m, 1H), 7.78-7.73 (m, 1H), 7.57-7.53 (m, 1H), 7.50-7.47 (m, 1H), 7.28-7.24 (m, 1H), 5.68 (s, br, 2H), 4.55 (hp, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.44 (d, 6H))

Stage 152.1.1 2-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-chloro-pyridin-3-ylamine (stage 152.1.2, 2.6 mmol) to give the title compound as a crude black solid. (degrading under the HPLC condition: t_(R) 1.57 min (Method A); M+H=255 MS-ES).

Stage 152.1.2 5-Bromo-2-chloro-pyridin-3-ylamine

A suspension of 5-bromo-2-chloro-3-nitropyridine (Combi-Blocks, San Diego, USA, 41.3 mmol) in concentrated HCl (45 ml) was cooled with an ice-bath. Was added portionwise over 1.5 h SnCl₂ dihydrate (124 mmol). The RM was stirred for 24 h at rt then poured on ice and basified with 6 M aqueous NaOH (125 ml). The resulting slurry was filtered and the solid was taken in aqueous NaHCO₃, sonicated and filtered. The solid was dissolved in EtOAc and water and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as an off-white solid. (HPLC: t_(R) 2.52 min (Method A); M+H=207 (BrCl pattern) MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 152.2 A

8-(5-Amino-6-chloro- pyridin-3-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 420 2.36 152.3 H

8-(5-Amino-6-chloro- pyridin-3-yl)-3-methyl- 1-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 434 2.43

Example 153.1 8-(6-Chloro-5-ethylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.101 mmol) and [2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-ethyl-amine (stage 153.1.1) to give the title compound as a yellow solid. (HPLC: t_(R) 2.74 min (Method A); M+H=462 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.13-8.08 (m, 1H), 7.98-7.93 (m, 1H), 7.76-7.73 (m, 1H), 7.58-7.54 (m, 1H), 6.97-6.93 (m, 1H), 5.72 (t, 1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.26 (qt, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.22 (t, 3H))

Stage 153.1.1 [2-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-ethyl-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-2-chloro-pyridin-3-yl)-ethyl-amine (stage 153.1.2, 3.71 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 2.17 min (Method A); M+H=283 MS-ES).

Stage 153.1.2 (5-Bromo-2-chloro-pyridin-3-yl)-ethyl-amine

The title compound was synthesized in a similar manner as described for (Stage 87.1.2.) using 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 4.34 mmol) to give the title compound as an oil (HPLC: t_(R) 3.38 min (Method A); M+H=235 (BrCl pattern) MS-ES). The following examples were synthesized in a similar manner as described for Example 1.1 using 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-ethyl-amine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 153.2 A

8-(6-Chloro-5- ethylamino-pyridin-3- yl)-1-(1,3-dimethyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 448 2.69 153.3 Q

8-(6-Chloro-5- ethylamino-pyridin-3- yl)-1-(3,5-dimethyl- isoxazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 448 2.88

Example 154.1 8-(5-Ethylamino-6-fluoro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.104 mmol) and ethyl-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (stage 154.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.63 min (Method A); M+H=446 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.11-8.07 (m, 1H), 7.96-7.91 (m, 1H), 7.55-7.52 (m, 1H), 7.48-7.45 (m, 1H), 7.00-6.95 (m, 1H), 5.96 (t, 1H), 3.78 (s, 3H), 3.59 (s, 3H), 3.20 (qt, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.23 (t, 3H))

Stage 154.1.1 Ethyl-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-2-fluoro-pyridin-3-yl)-ethyl-amine (stage 154.1.2, 2.283 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.92 min (Method A); M+H=267 MS-ES).

Stage 154.1.2 (5-Bromo-2-fluoro-pyridin-3-yl)-ethyl-amine

The title compound was synthesized in a similar manner as described for (Stage 87.1.2.) using 3-amino-5-bromo-2-fluoropyridine (Matrix Scientific, Columbia, S.C., USA, 3.14 mmol) to give the title compound as greenish solid (HPLC: t_(R) 3.20 min (Method A); M+H=219, 221 MS-ES).

The following example was synthesized in a similar manner as described for Example 1.1 using ethyl-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 154.2 Q

1-(3,5-Dimethyl- isoxazol-4-yl)-8-(5- ethylamino-6-fluoro- pyridin-3-yl)-3-methyl- 1,3-dihydro- imidazo[4,5- c]quinolin-2-one 433 2.76

Example 155.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester (stage 155.1.1, 0.041 mmol) in dioxane (0.33 ml) was treated with 1 M aqueous LiOH (0.082 ml) for 1.5 h at rt then was added 1 M aqueous LiOH (0.082 ml) and the RM was stirred for 2 h at rt. The RM was diluted with EtOAc and washed with sat. aqueous NaHCO₃, dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The pure fraction was basified with NaHCO₃, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a film. (HPLC: t_(R) 2.10 min (Method A); M+H=444 MS-ES; ¹H-NMR (d_(g)-DMSO, 400 MHz) 8.97 (s, 1H), 8.12-8.08 (m, 2H), 7.97-7.90 (m, 2H), 7.63-7.60 (m, 1H), 6.87 (s, 1H), 5.49 (t, 1H), 5.31 (t, 1H), 4.57 (d, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.19 (qt, 2H), 1.96 (s, 3H), 1.25 (t, 3H))

Stage 155.1.1 Acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.109 mmol) and acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester (stage 155.1.2) to give the title compound as an off-white solid. (HPLC: t_(R) 2.88 min (Method A); M+H=586 MS-ES)

Stage 155.1.2 Acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using acetic acid 5-bromo-3-(tert-butoxycarbonyl-ethyl-amino)-pyridin-2-ylmethyl ester (stage 155.1.3, 0.968 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 3.09 min (Method A); M+H=421 MS-ES).

Stage 155.1.3 Acetic acid 5-bromo-3-(tert-butoxycarbonyl-ethyl-amino)-pyridin-2-ylmethyl ester

(5-Bromo-2-methyl-1-oxy-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester (Stage 155.1.4, 1.467 mmol) in acetic anhydride (1.5 ml) was stirred under Ar for 35 min at 120° C. The RM was quenched with EtOH and stirred then diluted with water, neutralized with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (heptane/EtOAc 0% to 30%) to give after evaporation of the fractions containing the title compound an oil (HPLC: t_(R) 3.51 min (Method A); M+H=373, 375 MS-ES).

Stage 155.1.4 (5-Bromo-2-methyl-1-oxy-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester

A mixture of (5-bromo-2-methyl-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester (stage 155.1.5, 1.508 mmol) in dichloromethane (13 ml) and 65% m-chloroperbenzoic acid (3.02 mmol) was stirred for 4 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous Na₂CO₃, saturated aqueous NaHCO₃ (4×) and brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as an oil (HPLC: t_(R) 3.02 min (Method A); M+H=331, 333 MS-ES).

Stage 155.1.5 (5-Bromo-2-methyl-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester

A mixture of (5-bromo-2-methyl-pyridin-3-yl)-ethyl-amine (Stage 87.1.2, 1.634 mmol) and di-tertbutyl dicarbonate (Fluka, Buchs, Switzerland, 1.961 mmol) in THF (1.6 ml) was stirred for 1 h at rt and 3 h at 65° C. Was added di-tertbutyl dicarbonate (Fluka, Buchs, Switzerland, 1.961 mmol) and an extra stirring for 22 h at 65° C. to bring reaction to completion. The RM was diluted with EtOAc, washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 30%) to give after evaporation of the fractions containing the title compound an oil (HPLC: t_(R) 3.41 min (Method A); M+H=315, 317 MS-ES).

The following examples were synthesized in a similar manner as described for Example 155.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 155.2 F

8-(5-Ethylamino-6- hydroxymethyl- pyridin-3-yl)-1-(1- ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 458 2.15 155.3 G

8-(5-Ethylamino-6- hydroxymethyl- pyridin-3-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 472 2.21 155.4 H

8-(5-Ethylamino-6- hydroxymethyl- pyridin-3-yl)-3-methyl- 1-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 458 2.16

Example 156 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 155.1, 0.086 mmol) in DMF (0.5 ml) was treated with 55% NaH in oil (0.086 mmol) and the RM was stirred for 10 min at rt, then was added iodomethane (0.086 mmol) and the RM was stirred for 2 h at rt. The RM was quenched with water, diluted with DMF, filtered and purified by preparative HPLC. The pure fractions were basified with NaHCO₃, concentrated and extracted with CH₂Cl₂ (3×) and with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a film. (HPLC: t_(R) 2.24 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.08 (m, 2H), 7.98-7.91 (m, 2H), 7.64-7.61 (m, 1H), 6.90 (s, 1H), 5.32 (t, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 3.20 (qt, 2H), 1.97 (s, 3H), 1.23 (t, 3H))

Example 157 8-(5-Ethylamino-6-methoxymethyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 156.1 using 8-(5-ethylamino-6-hydroxymethyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 155.2) to give the title compound as an off-white solid. (HPLC: t_(R) 2.29 min (Method A); M+H=472 MS-ES; ¹H-NMR (de-DMSO, 400 MHz) 8.97 (s, 1H), 8.16 (s, 1H), 8.12-8.08 (m, 1H), 7.96-7.92 (m, 1H), 7.87-7.85 (m, 1H), 7.58-7.56 (m, 1H), 6.95-6.92 (m, 1H), 5.31 (t, 1H), 4.52 (s, 2H), 4.15 (q, 2H), 3.58 (s, 3H), 3.26 (s, 3H), 3.25-3.17 (m, 2H), 1.97 (s, 3H), 1.37 (t, 3H), 1.22 (t, 3H))

Example 158.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 155.1 using (5-bromo-2-methyl-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester (stage 158.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.02 min (Method A); M+H=430 MS-ES; ¹H-NMR (d_(g)-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.07 (m, 2H), 7.99-7.90 (m, 2H), 7.65-7.61 (m, 1H), 6.85-6.80 (m, 1H), 5.67 (q, br, 1H), 5.22 (br, 1H), 4.55 (d, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 2.83 (d, 3H), 1.97 (s, 3H))

Stage 158.1.1 (5-Bromo-2-methyl-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester

A solution of (5-bromo-2-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (Stage 158.1.2, 4.53 mmol) in DMF (20 ml) was cooled with an ice-bath and 55% NaH in oil (5.89 mmol) was added. The RM was stirred for 25 min at 0° C. then was added iodomethane (5.22 mmol). The RM was stirred for 2 h at rt then was quenched with aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with water (3×), with brine (3×), dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a brown solid (HPLC: t_(R) 3.20 min (Method A); M+H=301, 303 MS-ES).

Stage 158.1.2 (5-Bromo-2-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester

The title compound was synthesized in a similar manner as described for stage 155.1.5 using 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 7.86 mmol) to give the title compound as an oil (HPLC: t_(R) 2.88 min (Method A); M+H=287, 289 MS-ES).

The following examples were synthesized in a similar manner as described for Example 158.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 158.2 G

8-(6-Hydroxymethyl- 5-methylamino- pyridin-3-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 458 2.12 158.3 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(6- hydroxymethyl-5- methylamino-pyridin- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 450 2.20 158.4 H

8-(6-Hydroxymethyl- 5-methylamino- pyridin-3-yl)-3-methyl- 1-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 444 2.07 158.5 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-8-(6- hydroxymethyl-5- methylamino-pyridin- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 444 2.07

Example 159 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 156.1 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 158.1) to give the title compound as an off-white foam. (HPLC: t_(R) 2.15 min (Method A); M+H=444 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.12-8.08 (m, 2H), 7.99-7.91 (m, 2H), 7.65-7.62 (m, 1H), 6.85-6.82 (m, 1H), 5.57 (q, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.27 (s, 3H), 2.82 (d, 3H), 1.97 (s, 3H))

Example 160.1 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 156.1 using 1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 158.3) to give the title compound as an off-white solid. (HPLC: t_(R) 2.32 min (Method A); M+H=464 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.37 (s, 1H), 8.14-8.09 (m, 1H), 8.02-7.94 (m, 2H), 7.63-7.60 (m, 1H), 6.90-6.86 (m, 1H), 5.60 (q, br, 1H), 4.50 (s, 2H), 3.95 (s, 3H), 3.59 (s, 3H), 3.28 (s, 3H), 2.83 (d, 3H))

The following example was synthesized in a similar manner as described for Example 156.1 using the specified example as intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 160.2 158.5

1-(1-Ethyl-3-Methyl- 1H-pyrazol-4-yl)-8-(6- methoxymethyl-5- methylamino-pyridin- 3-yl)-3-methyl-1,3- dihydro-imidazol[4,5- c]quinolin-2-one 458 2.19

Example 161 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 87.1 using diethyl methylmalonate (Fluka, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 2.26 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.12-8.07 (m, 2H), 7.96-7.91 (m, 2H), 7.63-7.59 (m, 1H), 6.78-6.75 (m, 1H), 5.29 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.18 (qt, 2H), 2.67 (q, 2H), 1.97 (s, 3H), 1.25 (t, 3H), 1.20 (t, 3H))

Example 162 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-isopropylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 161 using (5-bromo-2-ethyl-pyridin-3-yl)-isopropyl-amine (Stage 162.1.1) to give the title compound as an off-white foam. (HPLC: t_(R) 2.34 min (Method A); M+H=456 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.12-8.07 (m, 2H), 7.95-7.90 (m, 2H), 7.61-7.58 (m, 1H), 6.81-6.78 (m, 1H), 4.88 (d, 1H), 3.88 (s, 3H), 3.76-3.62 (m, 1H), 3.58 (s, 3H), 2.67 (q, 2H), 1.97 (s, 3H), 1.25 (d, 3H), 1.21 (d, 3H), 1.19 (t, 3H))

Stage 162.1.1 (5-Bromo-2-ethyl-pyridin-3-yl)-isopropyl-amine

To solution of (5-bromo-2-ethyl-pyridin-3-yl)-isopropylidene-amine (Stage 162.1.2, 1.17 mmol) in dichloromethane (25 ml) was added AcOH (0.25 ml) and sodium triacetoxyborohydride (3.51 mmol). The reaction mixture was stirred for 4 h at rt. The RM was quenched with aqueous NaHCO₃ and extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and eluted (CH₂Cl₂/MeOH 0% to 3%). The fractions containing the product were purified by preparative HPLC. The fractions containing pure product were basified with NaHCO₃, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to the title compound as an oil (HPLC: t_(R) 2.40 min (Method A); M+H=243, 245 MS-ES).

Stage 162.1.2 (5-Bromo-2-ethyl-pyridin-3-yl)-isopropylidene-amine

To a solution of 5-bromo-2-ethyl-pyridin-3-ylamine (1.492 mmol), synthesized in a similar manner as described for 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4) using diethyl methylmalonate (HPLC: t_(R) 1.71 min (Method A); M+H=201, 203 MS-ES), in chloroform (0.75 ml) and 2-methoxypropene (Aldrich, Buchs, Switzerland, 7.46 mmol) were added triethylamine (1.492 mmol) and pyridinium para-toluensulfonate (0.149 mmol). The RM was stirred for 17 h at 100° C., then was quenched with aqueous Na₂CO₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a brown oil (M+H=241, 243 MS-ES).

Example 163 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methyl-5-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 163.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.10 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.12-8.06 (m, 2H), 7.96-7.92 (m, 1H), 7.89-7.87 (m, 1H), 7.62-7.60 (m, 1H), 6.73-6.70 (m, 1H), 5.51 (q, br, 1H), 3.88 (s, 3H), 3.57 (s, 3H), 2.80 (d, 3H), 2.31 (s, 3H), 1.97 (s, 3H))

Stage 163.1.1 Methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-2-methyl-pyridin-3-yl)-methyl-amine (stage 163.1.2, 1.194 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.64 min (Method A); M+H=249 MS-ES).

Stage 163.1.2 (5-Bromo-2-methyl-pyridin-3-yl)-methyl-amine

To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 3.81 mmol) in THF (25 ml) cooled with an ice-bath was added 1 M bis(trimethylsilyl)amide in THF (4.38 mmol). The RM was stirred for 1 h at rt then was added iodomethane (4.38 mmol). The RM was stirred for 1 h at rt. The RM was cooled with an ice-bath and was added 1 M bis(trimethylsilyl)amide in THF (1.9 mmol). The RM was stirred for 30 min at rt then was added iodomethane (1.9 mmol). The RM was stirred for 1 h at rt then was diluted with EtOAc and washed with aqueous Na₂CO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was taken in MeOH and separated by preparative HPLC. The first eluting pure fractions containing product were basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined fractions were washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a brown oil (HPLC: t_(R) 1.88 min (Method A); M+H=201, 203 MS-ES). The second eluting pure fractions, that contained (5-bromo-2-methyl-pyridin-3-yl)-dimethyl-amine side product, were basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined fractions were washed with brine, dried over Na₂SO₄, filtered and evaporated to give the title compound as a brown oil (HPLC: t_(R) 2.01 min (Method A); M+H=215, 217 MS-ES).

Example 164 8-(5-Dimethylamino-6-methyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and dimethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 164.1.1) to give the title compound as an off-white foam. (HPLC: t_(R) 2.15 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.30-8.27 (m, 1H), 8.13-8.08 (m, 2H), 7.99-7.94 (m, 1H), 7.59-7.56 (m, 1H), 7.33-7.30 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.72 (s, 6H), 2.50 (s, 3H), 1.97 (s, 3H))

Stage 164.1.1 Dimethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-2-methyl-pyridin-3-yl)-dimethyl-amine (stage 163.1.2, 1.255 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.93 min (Method A); M+H=263 MS-ES).

Example 165 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(ethyl-methyl-amino)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 165.1.1) to give the title compound as a white foam. (HPLC: t_(R) 2.26 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.95 (s, 1H), 8.32-8.29 (m, 1H), 8.13-8.09 (m, 2H), 7.99-7.94 (m, 1H), 7.61-7.58 (m, 1H), 7.35-7.32 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.97 (q, 2H), 2.71 (s, 3H), 2.45 (s, 3H), 1.97 (s, 3H), 1.09 (t, 3H))

Stage 165.1.1 Ethyl-methyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-2-methyl-pyridin-3-yl)-ethyl-methyl-amine (stage 165.1.2, 0.646 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 2.12 min (Method A); M+H=277 MS-ES).

Stage 165.1.2 (5-Bromo-2-methyl-pyridin-3-yl)-ethyl-methyl-amine

The title compound was synthesized in a similar manner as described for Stage 163.1.2 using (5-bromo-2-methyl-pyridin-3-yl)-ethyl-amine (Stage 87.1.2, 0.677 mmol) to give the title compound as a brown oil (HPLC: t_(R) 2.22 min (Method A); M+H=229, 231 MS-ES).

Example 166.1 8-(6-Amino-5-ethoxymethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 166.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.17 min (Method A); M+H=444 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.13 (s, 1H), 8.08-8.06 (m, 1H), 8.05-8.01 (m, 1H), 7.86-7.82 (m, 1H), 7.49-7.47 (m, 1H), 7.44-7.42 (m, 1H), 6.02 (s, br, 2H), 4.37 (s, 2H), 3.92 (s, 3H), 3.57 (s, 3H), 3.51 (q, 2H), 1.95 (s, 3H), 1.18 (t, 3H))

Stage 166.1.1 3-Ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-3-ethoxymethyl-pyridin-2-ylamine (stage 166.1.2, 1.082 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.72 min (Method A); M+H=279 MS-ES).

Stage 166.1.25-Bromo-3-ethoxymethyl-pyridin-2-ylamine

A solution of (2-amino-5-bromo-pyridin-3-yl)-methanol hydrobromide (Apollo, Cheshire, UK, 3.52 mmol) in DMF (15 ml) cooled with an ice-bath was treated with 55% NaH in oil (7.4 mmol) and the RM was stirred for 5 min at 00° C. and 30 min at rt, then was added iodoethane (3.87 mmol) and the RM was stirred for 1 h 15 min at rt. The RM was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO₃, with brine (2×), dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO₃, concentrated and extracted with CH₂Cl₂ (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a light yellow oil. (HPLC: t_(R) 2.07 min (Method A); M+H=231, 233 MS-ES)

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 166.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 166.2 F

8-(6-Amino-5- ethoxymethyl-pyridin- 3-yl)-1-(1-ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 458 2.22 166.3 G

8-(6-Amino-5- ethoxymethyl-pyridin- 3-yl)-1-(1-isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 472 2.29 166.4 K

8-(6-Amino-5- ethoxymethyl-pyridin- 3-yl)-1-(3-chloro-1- methyl-1H-pyrazol-4- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 464 2.33 166.5 H

8-(6-Amino-5- ethoxymethyl-pyridin- 3-yl)-3-methyl-1- (1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 458 2.21

Example 167 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxymethyl-6-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and [3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-ethyl-amine (Stage 167.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.30 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.19-8.16 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.44-7.41 (m, 2H), 6.07 (t, 1H), 4.39 (s, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.51 (q, 2H), 3.46-3.37 (m, 2H), 1.95 (s, 3H), 1.19 (t, 3H), 1.15 (t, 3H))

Stage 167.1.1 [3-Ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-ethyl-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-3-ethoxymethyl-pyridin-2-yl)-ethyl-amine (stage 167.1.2, 0.99 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.98 min (Method A); M+H=307 MS-ES).

Stage 167.1.2 (5-Bromo-3-ethoxymethyl-pyridin-2-yl)-ethyl-amine

The title compound was synthesized in a similar manner as described for Stage 87.1.2 using 5-bromo-3-ethoxymethyl-pyridin-2-ylamine (stage 166.1.2, 1.082 mmol) to give the title compound as a yellow oil. (HPLC: t_(R) 2.30 min (Method A); M+H=259, 261 MS-ES)

Example 168.1 8-(6-Amino-5-methoxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and 3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 168.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.19 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.20 (s, 1H), 8.06-8.01 (m, 2H), 7.85-7.80 (m, 1H), 7.53-7.50 (m, 1H), 7.44-7.41 (m, 1H), 5.99 (s, br, 2H), 4.54 (hp, 1H), 4.30 (s, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.95 (s, 3H), 1.47 (d, 6H))

Stage 168.1.1 3-Methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine

The title compound was synthesized in a similar manner as described for Stage 166.1.1-2 using iodomethane as replacement for iodoethane to give the title compound as a crude black soft solid. (degrading under the HPLC condition: t_(R) 1.47 min (Method A); M+H=265 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using 3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (Stage 168.1.1) and the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 168.2 F

8-(6-Amino-5- methoxymethyl- pyridin-3-yl)-1-(1- ethyl-3-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 444 2.12 168.3 K

8-(6-Amino-5- methoxymethyl- pyridin-3-yl)-1-(3- chloro-1-methyl-1H pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 472 2.29

Example 169.1 8-(6-Amino-5-hydroxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol), crude acetic acid 2-diacetylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl ester (stage 169.1.1, 0.92 mg) and PdCl₂(PPh₃)₂ (0.0057 mmol) in DMF (1.2 ml) and 1 M aqueous K₂CO₃ (0.245 ml) was stirred under argon at 105° C. for 1 h. Then the RM was cooled to rt and 2 M aqueous LiOH (0.245 ml) was added. The RM was stirred for 1 h 15 min at rt then quenched with 2 M aqueous HCl (0.245 ml), diluted with MeOH and purified directly by Prep.HPLC. The fractions containing product were collected together, basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.04 min (Method A); M+H=444 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.20 (s, 1H), 8.06-8.02 (m, 1H), 7.97-7.94 (m, 1H), 7.83-7.78 (m, 1H), 7.57-7.54 (m, 1H), 7.45-7.42 (m, 1H), 5.95 (s, br, 2H), 5.20 (t, 1H), 4.55 (hp, 1H), 4.37 (d, 2H), 3.57 (s, 3H), 1.95 (s, 3H), 1.47 (d, 6H))

Stage 169.1.1 Acetic acid 2-diacetylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl ester

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using acetic acid 2-diacetylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl ester (stage 169.1.2, 1.762 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 2.05 min (Method A); M+H=377 MS-ES).

Stage 169.1.2 Acetic acid 2-diacetylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl ester

To a suspension of 2-amino-5-bromo-3-hydroxymethylpyridine hydrobromide (Apollo, Cheshire, UK, 1.761 mmol) in dichloromethane (9 ml) were added triethylamine (7.92 mmol) and then acetyl chloride (5.81 mmol). The RM was stirred for 1.5 h at rt then was diluted with dichloromethane, washed with brine (2×), dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as an oil. (HPLC: t_(R) 1.69 min (Method A); M+H=329, 331 MS-ES).

The following examples were synthesized in a similar manner as described for Example 169.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 169.2 H

8-(6-Amino-5- hydroxymethyl- pyridin-3-yl)-3-methyl- 1-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 430 1.98 169.3 K

8-(6-Amino-5- hydroxymethyl- pyridin-3-yl)-1-(3- chloro-1-methyl-1H- pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 436 2.06

Example 170 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.125 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.1) to give the title compound as a beige solid. (HPLC: t_(R) 2.59 min (Method A); M+H=484 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.35-8.33 (m, 1H), 8.21 (s, 1H), 8.15-8.11 (m, 1H), 7.91-7.83 (m, 2H), 7.52-7.49 (m, 1H), 5.36-5.29 (m, 2H), 4.56 (qt, 1H), 3.58 (s, 3H), 3.35 (s, 3H), 1.95 (s, 3H), 1.46 (d, 6H))

Stage 170.1.1 1-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 6-bromo-1-methyl-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (stage 170.1.2, 0.30 mmol) to give the title compound as a crude brown soft solid. (degrading partially under the HPLC condition: t_(R) 1.87 and 3.68 min (Method A); M+H=291 MS-ES).

Stage 170.1.2 6-Bromo-1-methyl-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one

To a solution of 6-bromo-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.3, 0.707 mmol) in DMF (1.4 ml) was added 55% sodium hydride in oil (0.778 mmol). The RM was stirred for 5 min at rt then was added iodomethane (0.778 mmol) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc, washed with saturated NaHCO₃, with brine (3×), dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 70%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: t_(R) 2.64 min (Method A).

Stage 170.1.3 6-Bromo-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one

A mixture of 2-amino-5-bromo-3-hydroxymethylpyridine hydrobromide (Apollo, Cheshire, UK, 0.528 mmol) in dichloromethane (1.25 ml) and triethylamine (1.162 mmol) was cooled with an ice-bath. Was added to the RM trichloromethyl chloroformate (0.317 mmol) in dichloromethane and the RM was stirred for 30 min at 0° C. and 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 80%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: t_(R) 2.16 min (Method A); M+H=229, 231 MS-ES)

Example 171 8-(5-Hydroxymethyl-6-methylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 170, 0.04 mmol) in dioxane (0.32 ml) and 1 M aqueous LiOH (0.08 ml) was stirred for 1.5 h at rt. The reaction mixture was diluted with EtOAc and quenched with 2 M aqueous HCl (0.12 ml) and water. Then was added saturated aqueous NaHCO₃ and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as an off-white solid. (HPLC: t_(R) 2.09 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.20 (s, 1H), 8.09-8.01 (m, 2H), 7.83-7.79 (m, 1H), 7.52-7.49 (m, 1H), 7.45-7.42 (m, 1H), 6.10 (q, br, 1H), 5.21 (t, 1H), 4.56 (qt, 1H), 4.38 (d, 2H), 3.57 (s, 3H), 2.86 (d, 3H), 1.95 (s, 3H), 1.49-1.45 (m, 6H))

Example 172 8-(5-Cyclobutylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and cyclobutyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 172.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.29 min (Method A); M+H=440 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.07 (m, 2H), 7.93-7.84 (m, 3H), 7.58-7.55 (m, 1H), 6.80-6.76 (m, 1H), 6.34 (d, 1H), 3.94-3.85 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 2.44-2.34 (m, 2H), 1.96 (s, 3H), 1.93-1.73 (m, 4H))

Stage 172.1.1 Cyclobutyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-pyridin-3-yl)-cyclobutyl-amine (stage 172.1.2, 2.349 mmol) to give the title compound as a crude brown foam. (degrading under the HPLC condition: t_(R) 2.06 min (Method A); M+H=275 MS-ES).

Stage 172.1.2 (5-Bromo-pyridin-3-yl)-cyclobutyl-amine

A mixture of 3-bromo-5-fluoropyridine (Frontier Scientific, Logan, USA, 5.63 mmol) and cyclobutylamine (Fluka, Buchs, Switzerland, 12.38 mmol) in NMP (8 ml) was heated under microwave irradiation for 1 h at 190° C. and for 5.5 h at 200° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO₃, with brine (3×), dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as an off-white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=227, 229 MS-ES)

Example 173 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(isopropyl-methyl-amino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using N-isopropylmethylamine (Fluka, Buchs, Switzerland, 7.61 mmol) as replacement of the cyclobutylamine to give the title compound as a white solid. (HPLC: t_(R) 2.29 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98-8.97 (m, 1H), 8.18-8.15 (m, 1H), 8.13-8.08 (m, 2H), 8.03-8.00 (m, 1H), 7.98-7.93 (m, 1H), 7.61-7.58 (m, 1H), 7.05-7.03 (m, 1H), 4.20 (qt, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 2.77 (s, 3H), 1.97 (s, 3H), 1.17 (d, 3H), 1.16 (d, 3H))

Example 174 8-[5-(Cyclobutyl-methyl-amino)-pyridin-3-yl]-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and Cyclobutyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 174.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.39 min (Method A); M+H=454 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.15-8.04 (m, 4H), 7.96-7.92 (m, 1H), 7.60-7.57 (m, 1H), 7.06-7.03 (m, 1H), 4.17 (qt, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.89 (s, 3H), 2.28-2.02 (m, 4H), 1.97 (s, 3H), 1.81-1.63 (m, 2H))

Stage 174.1.1 Cyclobutyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-pyridin-3-yl)-cyclobutyl-methyl-amine (stage 174.1.2, 2.349 mmol) to give the title compound as a crude black sticky oil. (degrading under the HPLC condition: t_(R) 2.27 min (Method A); M+H=289 MS-ES).

Stage 174.1.2 (5-Bromo-pyridin-3-yl)-cyclobutyl-methyl-amine

The title compound was synthesized in a similar manner as described for Stage 163.1.2 using (5-bromo-pyridin-3-yl)-cyclobutyl-amine (stage 172.1.2, 0.427 mmol) to give the title compound as a crude brown oil. (HPLC: t_(R) 2.49 min (Method A); M+H=241, 243 MS-ES).

Example 175.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(5-morpholin-4-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using morpholine (Fluka, Buchs, Switzerland, 6.02 mmol) as replacement of the cyclobutylamine to give the title compound as an off-white solid. (HPLC: t_(R) 2.10 min (Method A); M+H=456 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.34-8.31 (m, 1H), 8.20-8.17 (m, 1H), 8.14-8.09 (m, 2H), 8.01-7.96 (m, 1H), 7.60-7.58 (m, 1H), 7.29-7.26 (m, 1H), 3.88 (s, 3H), 3.82-3.77 (m, 4H), 3.58 (s, 3H), 3.27-3.21 (m, 4H), 1.95 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 175.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 175.2 C

1-(2,5-Dimethyl-2H- pyrazol-3-yl)-3- methyl-8-(5- morpholin-4-yl- pyridin-3-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 456 2.26 175.3 Stage 103.1.1

1-[1-(2-Hydroxy- ethyl)-3-methyl-1H- pyrazol-4-yl]-3- methyl-8-(5- morpholin-4-yl- pyridin-3-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 486 2.05

Example 176 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(ethyl-methyl-amino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using N-ethylmethylamine (Aldrich, Buchs, Switzerland, 5.75 mmol) as replacement for the cyclobutylamine to give the title compound as a yellowish solid. (HPLC: t_(R) 2.21 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.07 (m, 3H), 8.02-7.99 (m, 1H), 7.98-7.93 (m, 1H), 7.62-7.58 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 3.53-3.43 (m, 2H), 2.95 (s, 3H), 1.96 (s, 3H), 1.07 (t, 3H))

Example 177.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using isopropylamine (Aldrich, Buchs, Switzerland, 6.27 mmol) as replacement of the cyclobutylamine to give the title compound as an off-white solid. (HPLC: t_(R) 2.21 min (Method A); M+H=428 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.07 (m, 2H), 7.96-7.92 (m, 1H), 7.90-7.84 (m, 2H), 7.59-7.56 (m, 1H), 6.87-6.84 (m, 1H), 5.87 (d, 1H), 3.88 (s, 3H), 3.63 (oc, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.22-1.13 (m, 6H))

The following example was synthesized in a similar manner as described for Example 177.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 177.2 N

8-(5-Isopropylamino- pyridin-3-yl)-1-[1-(2- methoxy-ethyl)-3,5- dimethyl-1H-pyrazol- 4-yl]-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 486 2.33

Example 178 8-(5-Dimethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using 2 M dimethylamine in THF (Aldrich, Buchs, Switzerland, 6.11 mmol) as replacement of the cyclobutylamine to give the title compound as a yellowish solid. (HPLC: t_(R) 2.12 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.04 (m, 4H), 7.99-7.94 (m, 1H), 7.62-7.59 (m, 1H), 7.02-6.99 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.00 (s, 6H), 1.96 (s, 3H))

Example 179 8-(5-Azetidin-1-yl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using azetidine (Fluka, Buchs, Switzerland, 8.79 mmol) as replacement of the cyclobutylamine to give the title compound as a yellowish solid. (HPLC: t_(R) 2.18 min (Method A); M+H=426 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.05 (m, 3H), 7.97-7.92 (m, 1H), 7.81-7.77 (m, 1H), 7.60-7.57 (m, 1H), 6.78-6.74 (m, 1H), 3.98-3.86 (m, 7H), 3.58 (s, 3H), 2.39 (qt, 2H), 1.96 (s, 3H))

Example 180.1 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 172 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.071 mmol) and 8 M methylamine in ethanol (Fluka, Buchs, Switzerland, 6.48 mmol) as replacement of the cyclobutylamine to give the title compound as an off-white solid. (HPLC: t_(R) 2.08 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.17 (s, 1H), 8.12-8.08 (m, 1H), 7.94-7.92 (m, 1H), 7.91-7.87 (m, 1H), 7.86-7.84 (m, 1H), 7.57-7.55 (s, 1H), 6.89-6.86 (s, 1H), 6.05 (q, br, 1H), 4.16 (q, 2H), 3.58 (s, 3H), 2.75 (d, 3H), 1.97 (s, 3H), 1.39 (t, 3H))

The following example was synthesized in a similar manner as described for Example 180.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 180.2 G

1-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-8-(5- methylamino-pyridin- 3-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 428 2.15

Example 181 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 181.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.20 min (Method A); M+H=433 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.36-8.32 (m, 2H), 8.17-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.61-7.57 (m, 1H), 7.47-7.44 (m, 1H), 4.89-4.73 (m, 2H), 4.48-4.36 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))

Stage 181.1.1 3-(2-Fluoro-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 58.1.1 using 2-fluoroethanol (Aldrich, Buchs, Switzerland, 1.672 mmol) as replacement for isopropanol to give the title compound as a crude brown sticky oil. (degrading under HPLC condition: t_(R) 2.10 min (Method A); M+H=268 MS-ES).

Example 182 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-1-fluoromethyl-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-1-fluoromethyl-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 182.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=465 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.40-8.37 (m, 1H), 8.36-8.33 (m, 1H), 8.16-8.10 (m, 2H), 8.02-7.97 (m, 1H), 7.59-7.54 (m, 2H), 5.24-5.08 (m, 1H), 4.91-4.65 (m, 4H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H))

Stage 182.1.1 3-(2-Fluoro-1-fluoromethyl-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 58.1.1 using 1,3-difluoro-2-propanol (Aldrich, Buchs, Switzerland, 1.672 mmol) as replacement for isopropanol to give the title compound as a crude black oil. (degrading under HPLC condition: t_(R) 2.00 min (Method A); M+H=300 MS-ES).

Example 183 8-(5-Difluoromethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 183.1.1) to give the title compound as a white foam. (HPLC: t_(R) 2.48 min (Method A); M+H=437 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.61-8.59 (m, 1H), 8.52-8.50 (m, 1H), 8.17-8.13 (m, 2H), 8.02-7.98 (m, 1H), 7.74-7.71 (m, 1H), 7.61-7.59 (m, 1H), 7.39 (t, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 1.95 (s, 3H))

Stage 183.1.1 3-Difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 3-bromo-5-difluoromethoxy-pyridine (stage 183.1.2, 0.192 mmol) to give the title compound as a crude brown oil. (degrading under the HPLC condition: t_(R) 2.27 min (Method A); M+H=227 MS-ES).

Stage 183.1.2 3-Bromo-5-difluoromethoxy-pyridine

A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 1.394 mmol), sodium chlorodifluoroacetate (Aldrich, Buchs, Switzerland, 1.672 mmol) and potassium carbonate (2.79 mmol) in acetonitrile (10 ml) was refluxed for 4 h 45 min. The reaction was cooled and diluted with dichloromethane, washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated to give the title compound as a brown oil. (HPLC: t_(R) 2.91 min (Method A); M+H=224, 226 MS-ES).

Example 184 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 84 using methanol (Fluka, Buchs, Switzerland) as replacement for the isopropanol to give the title compound as a white solid. (HPLC: t_(R) 2.10 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.20-8.17 (m, 1H), 8.14-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.59 (m, 1H), 7.32-7.29 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.59 (s, 3H), 2.39 (s, 3H), 1.98 (s, 3H))

Example 185.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-hydroxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 84 using dioxane/water 1:1 as replacement for the isopropanol to give the title compound as a white solid. (HPLC: t_(R) 1.98 min (Method A); M+H=401 MS-ES; MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.97 (s, 1H), 8.97 (s, 1H), 8.14-8.09 (m, 2H), 7.99-7.96 (m, 1H), 7.82-7.77 (m, 1H), 7.55-7.52 (m, 1H), 7.21-7.18 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 2.36 (s, 3H), 1.96 (s, 3H))

The following example was synthesized in a similar manner as described for Example 185.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 185.2 C

1-(2,5-Dimethyl-2H- pyrazol-3-yl)-8-(5- hydroxy-6-methyl- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 401 2.14

Example 186 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 84 using diethyl methylmalonate (Fluka, Buchs, Switzerland) as replacement for the diethyl malonate to give the title compound as a white solid. (HPLC: t_(R) 2.44 min (Method A); M+H=467 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.23-8.20 (m, 1H), 8.13-8.09 (m, 2H), 8.01-7.96 (m, 1H), 7.61-7.58 (m, 1H), 7.31-7.28 (m, 1H), 4.75 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.75 (q, 2H), 1.98 (s, 3H), 1.37-1.33 (m, 6H), 1.19 (t, 3H))

Example 187 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-ethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 186 using ethanol as replacement for isopropanol to give the title compound as a white solid. (HPLC: t_(R) 2.32 min (Method A); M+H=443 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.25-8.22 (m, 1H), 8.14-8.09 (m, 2H), 8.02-7.98 (m, 1H), 7.62-7.59 (m, 1H), 7.30-7.27 (m, 1H), 4.24-4.10 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 2.77 (q, 2H), 1.97 (s, 3H), 1.43 (t, 3H), 1.20 (t, 3H))

Example 188 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-hydroxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 186 using dioxane/water 1:1 as replacement for isopropanol to give the title compound as an off-white solid. (HPLC: t_(R) 2.07 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.98 (s, br, 1H), 8.97 (s, 1H), 8.14-8.08 (m, 2H), 8.03-7.99 (m, 1H), 7.82-7.76 (m, 1H), 7.55-7.52 (m, 1H), 7.20-7.17 (m, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 2.73 (q, 2H), 1.96 (s, 3H), 1.18 (t, 3H))

Example 189 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-1-fluoromethyl-ethoxy)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(2-fluoro-1-fluoromethyl-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 189.1.1) to give the title compound as a white foam. (HPLC: t_(R) 2.26 min (Method A); M+H=479 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.17 (m, 1H), 8.14-8.10 (m, 2H), 8.00-7.95 (m, 1H), 7.58-7.52 (m, 2H), 5.16-5.01 (m, 1H), 4.92-4.66 (m, 4H), 3.89 (s, 3H), 3.58 (s, 3H), 2.41 (s, 3H), 1.97 (s, 3H))

Stage 189.1.1 3-(2-Fluoro-1-fluoromethyl-ethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 182.1.1 using 5-bromo-2-methyl-pyridin-3-ol (stage 189.1.2) as replacement for 3-bromo-5-hydroxypyridine to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 2.06 min (Method A); M+H=314 MS-ES).

Stage 189.1.2 5-Bromo-2-methyl-pyridin-3-ol

The title compound was synthesized in a similar manner as described for Stage 84.1.2 using dioxane/water 1:1 as replacement for isopropanol to give the title compound as an orange solid. (HPLC: t_(R) 1.41 min (Method A); M+H=188, 190 MS-ES).

Example 190 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and [3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methanol (Stage 190.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.19 min (Method A); M+H=459 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.23 (m, 1H), 8.15-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.59 (m, 1H), 7.40-7.37 (m, 1H), 4.84 (br, 1H), 4.76 (hp, 1H), 4.55 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.36-1.31 (m, 6H))

Stage 190.1.1 [3-Isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methanol

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-3-isopropoxy-pyridin-2-yl)-methanol (stage 190.1.2, 0.546 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 2.06 min (Method A)).

Stage 190.1.2 (5-Bromo-3-isopropoxy-pyridin-2-yl)-methanol

To a solution of 5-bromo-3-isopropoxy-2-methyl-pyridine 1-oxide (Stage 190.1.3, 2.054 mmol) in THF (13 ml) was added trifluoroacetic anhydride (10.27 mmol). The RM was stirred for 4 h at rt. The RM was evaporated to dryness. The residue was treated with saturated aqueous NaHCO₃ (20 ml), stirred for 15 h at rt and then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing the product are basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to give a yellowish slowly crystallizing solid. (HPLC: t_(R) 2.21 min (Method A); M+H=246, 248 MS-ES).

Stage 190.1.3 5-Bromo-3-isopropoxy-2-methyl-pyridine 1-oxide

The title compound was synthesized in a similar manner as described for Stage 155.1.4 using 5-bromo-3-isopropoxy-2-methyl-pyridine (Stage 84.1.2, 2.108 mmol) as replacement for (5-bromo-2-methyl-pyridin-3-yl)-ethyl-carbamic acid tert-butyl ester to give the title compound as a slowly crystallizing orange solid. (HPLC: t_(R) 2.75 min (Method A); M+H=246, 248 MS-ES).

Example 191.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 191.1.1) to give the title compound as a white foam. (HPLC: t_(R) 2.41 min (Method A); M+H=473 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.25 (m, 1H), 8.15-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.60 (m, 1H), 7.42-7.40 (m, 1H), 4.77 (hp, 1H), 4.47 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H), 1.37-1.32 (m, 6H))

Stage 191.1.1 3-Isopropoxy-2-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-3-isopropoxy-2-methoxymethyl-pyridine (stage 191.1.2, 0.142 mmol) to give the title compound as a crude brown oil. (degrading under the HPLC condition: t_(R) 2.40 min (Method A); M+H=308 MS-ES).

Stage 191.1.2 5-Bromo-3-isopropoxy-2-methoxymethyl-pyridine

To a solution of (5-bromo-3-isopropoxy-pyridin-2-yl)-methanol (stage 190.1.2, 0.61 mmol) in DMF (3 ml) was added 55% NaH in oil (0.688 mmol) was added. The RM was stirred for 30 min at rt then was added iodomethane (0.684 mmol). The RM was stirred for 2.5 h at rt then was quenched with MeOH and purified by preparative HPLC. The fractions containing product were combined, basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a yellow oil. (HPLC: t_(R) 2.83 min (Method A); M+H=260, 262 MS-ES).

The following example was synthesized in a similar manner as described for Example 191.1 using the specified intermediate.

HPLC MS-ES t_(R) Example Intermed. structure Name of the example (M + H) (min) 191.2 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-8- (5-isopropoxy-6- methoxymethyl- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 487 2.49

Example 192 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-1-fluoromethyl-ethoxy)-6-hydroxymethyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 190 using 5-bromo-3-(2-fluoro-1-fluoromethyl-ethoxy)-2-methyl-pyridine (Stage 192.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.15 min (Method A); M+H=495 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.29-8.26 (m, 1H), 8.15-8.10 (m, 2H), 8.02-7.98 (m, 1H), 7.63-7.58 (m, 2H), 5.19-5.04 (m, 1H), 4.93 (t, 1H), 4.91-4.66 (m, 4H), 4.60 (d, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))

Stage 192.1.1 5-Bromo-3-(2-fluoro-1-fluoromethyl-ethoxy)-2-methyl-pyridine

The title compound was synthesized in a similar manner as described for stage 58.1.2 using 5-bromo-2-methyl-pyridin-3-ol (stage 189.1.2, 2.234 mmol) and 1,3-difluoro-2-propanol (Aldrich, Buchs, Switzerland, 2.68 mmol) to give the title compound as a yellow oil. (HPLC: t_(R) 2.41 min (Method A); M+H=266, 268 MS-ES).

Example 193 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 190 using methanol as replacement for isopropanol to give the title compound as a white foam. (HPLC: t_(R) 1.99 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.28-8.25 (m, 1H), 8.15-8.11 (m, 2H), 8.05-8.01 (m, 1H), 7.64-7.62 (m, 1H), 7.40-7-37 (m, 1H), 4.90 (t, 1H), 4.56 (d, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.98 (s, 3H))

Example 194.1 8-(6-Hydroxymethyl-5-methoxy-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 169.1 using acetic acid 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester (stage 194.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.13 min (Method A); M+H=459 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.22-8.11 (m, 3H), 8.03-7.98 (m, 1H), 7.58-7.54 (m, 1H), 7.48-7-45 (m, 1H), 4.96 (t, 1H), 4.54 (d, 2H), 4.52 (hp, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 1.99 (s, 3H), 1.46-1.40 (m, 6H))

Stage 194.1.1 Acetic acid 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using acetic acid 5-bromo-3-methoxy-pyridin-2-ylmethyl ester (stage 194.1.2, 0.142 mmol) to give the title compound as a crude brown oil. (degrading under the HPLC condition: t_(R) 2.54, 3.69 min (Method A); M+H=308 MS-ES).

Stage 194.1.2 Acetic acid 5-bromo-3-methoxy-pyridin-2-ylmethyl ester

To a mixture of (5-bromo-3-methoxy-pyridin-2-yl)-methanol (Stage 194.1.3, 2.79 mmol) and triethylamine (4.18 mmol) in dichloromethane was added slowly acetyl chloride (3.35 mmol) and the RM was stirred for 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 60%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: t_(R) 2.72 min (Method A); M+H=260, 262 MS-ES)

Stage 194.1.3 (5-Bromo-3-methoxy-pyridin-2-yl)-methanol

The title compound was synthesized in a similar manner as described for Stage 190.1.2 using methanol as replacement for isopropanol to give the title compound as an off-white solid. (HPLC: t_(R) 1.76 min (Method A); M+H=218, 220 MS-ES).

The following example was synthesized in a similar manner as described for Example 194.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 194.2 K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-(6- hydroxymethyl-5- methoxy-pyridin-3- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 451 2.18

Example 195.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 191 using (5-bromo-3-methoxy-pyridin-2-yl)-methanol (Stage 194.1.3) to give the title compound as a white foam. (HPLC: t_(R) 2.21 min (Method A); M+H=445 MS-ES; ¹H-NMR (CDCl₃, 400 MHz) 8.81 (s, 1H), 8.40-8.38 (m, 1H), 8.31-8.24 (m, 1H), 7.91-7.86 (m, 1H), 7.73-7.70 (m, 1H), 7.66-7.64 (m, 1H), 7.19-7.17 (m, 1H), 4.68 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 3.70 (s, 3H), 3.53 (s, 3H), 2.14 (s, 3H))

The following examples were synthesized in a similar manner as described for Example 195.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 195.2 G

1-(1-Isopropyl-3- methyl-1H-pyrazol-4- yl)-8-(5-methoxy-6- methoxymethyl- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 473 2.37 195.3 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-8- (5-methoxy-6- methoxymethyl- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 459 2.28 195.4 K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-(5-methoxy-6- methoxymethyl- pyridin-3-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 459 2.28

Example 196.1 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-ethoxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 195.1 using iodoethane as replacement for iodomethane to give the title compound as a white foam. (HPLC: t_(R) 2.51 min (Method A); M+H=479 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.02 (s, 1H), 8.38-8.37 (m, 1H), 8.31-8.29 (m, 1H), 8.17-8.14 (m, 1H), 8.07-8.03 (m, 1H), 7.63-7.61 (m, 1H), 7.47-7.45 (m, 1H), 4.53 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.60 (s, 3H), 3.52 (q, 2H), 1.11 (t, 3H))

The following example was synthesized in a similar manner as described for Example 196.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 196.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-(6- ethoxymethyl-5- methoxy-pyridin-3- yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 459 2.31

Example 197.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 191 using (5-bromo-3-ethoxy-pyridin-2-yl)-methanol (Stage 197.1.2) to give the title compound as a white foam. (HPLC: t_(R) 2.33 min (Method A); M+H=459 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.28-8.26 (m, 1H), 8.15-8.10 (m, 2H), 8.04-8.00 (m, 1H), 7.64-7.61 (m, 1H), 7.41-7.38 (m, 1H), 4.49 (s, 2H), 4.22-4.14 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 3.31 (s, 3H), 1.97 (s, 3H), 1.41 (t, 3H))

Stage 197.1.2 (5-Bromo-3-ethoxy-pyridin-2-yl)-methanol

The title compound was synthesized in a similar manner as described for Stage 190.1.2 using ethanol as replacement for isopropanol to give the title compound as an orange solid. (HPLC: t_(R) 2.03 min (Method A); M+H=232, 234 MS-ES).

The following example was synthesized in a similar manner as described for Example 197.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 197.2 G

8-(5-Ethoxy-6- methoxymethyl- pyridin-3-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 487 2.49

Example 198 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-trideuteromethoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 197.1 using d₃-iodomethane (Aldrich, Buchs, Switzerland) as replacement for iodomethane to give the title compound as an off-white foam. (HPLC: t_(R) 2.33 min (Method A); M+H=462 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.29-8.26 (m, 1H), 8.15-8.11 (m, 2H), 8.04-8.00 (m, 1H), 7.64-7.61 (m, 1H), 7.41-7.38 (m, 1H), 4.49 (s, 2H), 4.22-4.14 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.41 (t, 3H))

Example 199 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-trideuteromethoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A solution of 1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 194.2, 0.033 mmol) in DMF (0.4 ml) was treated with 55% NaH in oil (0.037 mmol) and the RM was stirred for 5 min at rt, then was added d₃-iodomethane (Aldrich, Buchs, Switzerland, 0.037 mmol) and the RM was stirred for 30 min at rt. The RM was quenched with water, diluted with DMF, filtered and purified by preparative HPLC. The pure fractions were basified with NaHCO₃, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a foam. (HPLC: t_(R) 2.40 min (Method A); M+H=468 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.02 (s, 1H), 8.37 (s, 1H), 8.32-8.30 (m, 1H), 8.17-8.13 (m, 1H), 8.07-8.03 (m, 1H), 7.63-7.61 (s, 1H), 7.48-7.45 (m, 1H), 4.49 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.60 (s, 3H))

Example 200 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-hydroxymethyl-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a solution of 5-[1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid methyl ester (stage 200.1, 0.176 mmol) in THF (2 ml) cooled with an ice-bath was added dropwise a 1 M solution of LiAlH₄ in THF (0.150 mmol). The reaction mixture was stirred for 1 h 15 min at rt, then quenched with water, diluted with EtOAc and filtered over Celite. The filtrate was washed with saturated aqueous NaHCO₃, with water, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was dissolved in MeOH/TFA and purified by preparative HPLC. The fractions containing pure product were basified with NaHCO₃ and concentrated. The precipitate was filtered, washed with water (2×) and dried under vacuum to give the title compound as a white solid. (HPLC: t_(R) 2.53 min (Method A); M+H=451 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.41 (s, 1H), 8.30-8.27 (m, 1H), 8.14-8.10 (m, 1H), 7.98-7.93 (m, 1H), 7.84-7.81 (m, 1H), 7.53-7.50 (m, 1H), 5.32 (t, 1H), 4.51 (d, 2H), 4.01 (s, 3H), 3.92 (s, 3H), 3.59 (s, 3H))

Stage 200.1.1 5-[1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid methyl ester

The title compound was synthesized in a similar manner as described for Example 1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 2-methoxy-3-(carbomethoxy)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.75 min (Method A); M+H=479 MS-ES).

Example 201 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 156 using 1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-hydroxymethyl-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 200, 0.081 mmol) to give the title compound as a white foam. (HPLC: t_(R) 2.82 min (Method A); M+H=465 MS-ES; ¹H-NMR (de-DMSO, 400 MHz) 8.99 (s, 1H), 8.40 (s, 1H), 8.35-8.32 (m, 1H), 8.14-8.10 (m, 1H), 7.98-7.93 (m, 1H), 7.75-7.72 (m, 1H), 7.50-7.47 (m, 1H), 4.43 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.59 (s, 3H), 3.40 (s, 3H))

Example 202 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 201 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) to give the title compound as a yellow solid. (HPLC: t_(R) 2.36 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.31-8.28 (m, 1H), 8.13 (s, 1H), 8.11-8.07 (m, 1H), 7.94-7.90 (m, 1H), 7.72-7.69 (m, 1H), 7.54-7.51 (m, 1H), 4.42 (s, 2H), 3.92 (s, 3H), 3.92 (s, 3H), 3.58 (s, 3H), 3.39 (s, 3H), 1.95 (s, 3H))

Example 203 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 104 using 1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 16.5, 0.085 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=435 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.02 (s, 1H), 8.67-8.65 (m, 1H), 8.40 (s, 1H), 8.17-8.13 (m, 1H), 8.01-7.91 (m, 2H), 7.56-7.51 (m, 2H), 4.54 (s, 2H), 3.99 (s, 3H), 3.60 (s, 3H), 3.39 (s, 3H))

Example 204 8-(5,6-Dimethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 93.1 using 2-chloro-3-methoxy-pyridine (Apollo, Cheshire, UK, 7.1 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.52 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.12-8.07 (m, 2H), 7.99-7.95 (m, 1H), 7.92-7.90 (m, 1H), 7.55-7.53 (m, 1H), 7.25-7.23 (m, 1H), 3.90 (s, 3H), 3.89 (s, 6H), 3.58 (s, 3H), 1.98 (s, 3H))

Example 205 1-[1-(2-Azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 205.1.1, 0.067 mmol) and 3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 58.1.1, 0.102 mmol) to give the title compound as a white foam. (HPLC: t_(R) 2.35 min (Method A); M+H=512 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.34-8.32 (m, 1H), 8.24-8.21 (m, 1H), 8.13-8.09 (m, 2H), 8.01-7.96 (m, 1H), 7.67-7.64 (m, 1H), 7.38-7.35 (m, 1H), 4.91-4.73 (m, 3H), 4.18-4.07 (m, 2H), 3.91-3.78 (m, 2H), 3.58 (s, 3H), 2.22-2.05 (m, 2H), 1.98 (s, 3H), 1.33 (d, 3H), 1.31 (d, 3H))

Stage 205.1.1 1-[1-(2-Azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-bromo-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Stage 134.1 using azetidine (Fluka, Buchs, Switzerland) as replacement for N-methylpiperazine to give the title compound as a white solid. (HPLC: t_(R) 2.28 min (Method A); M+H=441, 443 MS-ES).

Example 206.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethylamino-5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 205.1.1, 0.067 mmol) and ethyl-[3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 206.1.1) to give the title compound as a yellow solid. (HPLC: t_(R) 2.20 min (Method A); M+H=458 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.22-8.18 (m, 1H), 8.13 (s, 1H), 8.05-8.00 (m, 1H), 7.88-7.84 (m, 1H), 7.45-7.40 (m, 2H), 6.09 (t, 1H), 4.38-4.30 (m, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 3.33 (s, 3H), 1.95 (s, 3H), 1.14 (t, 3H))

Stage 206.1.1 Ethyl-[3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 167.1.1 using iodomethane as replacement for iodoethane to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.81 min (Method A); M+H=293 MS-ES).

The following example was synthesized in a similar manner as described for Example 206.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 206.2 H

8-(6-Ethylamino-5- methoxymethyl- pyridin-3-yl)-3- methyl-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 472 2.24

Example 207 8-(2-Dimethylamino-pyrimidin-5-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 109 using 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=401 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.66 (s, br, 1H), 8.69 (s, 1H), 8.46 (s, 2H), 8.10 (s, 1H), 8.05-8.00 (m, 1H), 7.87-7.82 (m, 1H), 7.43-7.40 (m, 1H), 3.90 (s, 3H), 3.16 (s, 6H), 1.96 (s, 3H))

Example 208 8-(5-Amino-6-ethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Stage A2 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 208.1.1, 0.06 mmol) to give the title compound after purification as a white foam (HPLC: t_(R) 2.06 min (Method A); M+H=414 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.13-8.07 (m, 2H), 7.79-7.74 (m, 2H), 7.54-7.51 (m, 1H), 7.06-7.03 (m, 1H), 5.18 (s, br, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 2.64 (q, 2H), 1.96 (s, 3H), 1.19 (t, 3H))

Stage 208.1.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-ethyl-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 208.1.2) to give the title compound as a yellow foam. (HPLC: t_(R) 2.72 min (Method A); M+H=444 MS-ES).

Stage 208.1.2 2-Ethyl-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-2-ethyl-3-nitro-pyridine (stage 208.1.3, 0.493 mmol) to give the title compound as a crude brown oil. (degrading under the HPLC condition: t_(R) 2.65 min (Method A); M+H=279 MS-ES).

Stage 208.1.3 5-Bromo-2-ethyl-3-nitro-pyridine

The title compound was synthesized in a similar manner as described for Stage 75.1.5 using diethyl methylmalonate (Fluka, Buchs, Switzerland) as replacement for diethyl malonate to give the title compound as a brown oil. (HPLC: t_(R) 3.34 min (Method A); M+H=231, 233 MS-ES).

Example 209 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (ABCR, Karlsruhe, Germany) to give the title compound as a yellow foam. (HPLC: t_(R) 2.15 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.13 (s, 1H), 8.03-7.99 (m, 1H), 7.89-7.82 (m, 2H), 7.40-7.37 (m, 1H), 6.97-6.94 (m, 1H), 4.25 (t, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.47 (t, 2H), 3.06 (s, 3H), 1.95 (s, 3H))

Example 210 8-(5-Ethylamino-6-methyl-pyridin-3-yl)-1-[1-(2-hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-Bromo-1-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 210.1.1) and ethyl-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 87.1.1) to give the title compound as an off-white solid; deprotection of the silyl group occurred during the purification step. (HPLC: t_(R) 2.16 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.10-8.06 (m, 1H), 7.94-7.90 (m, 1H), 7.85-7.82 (m, 1H), 7.55-7.52 (m, 1H), 6.83-6.80 (m, 1H), 5.21 (t, 1H), 4.92 (t, 1H), 4.21-4.03 (m, 2H), 3.81-3.67 (m, 2H), 3.59 (s, 3H), 3.24-3.14 (m, 2H), 2.32 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H), 1.24 (t, 3H))

Stage 210.1.2 8-Bromo-1-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3,5-dimethyl-1H-pyrazol-4-yl}-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for intermediate N using (2-bromoethoxy)-tertbutyldimethylsilane (Frontier Scientific, Logan, USA) as replacement for the 2-bromoethyl methyl ether to give the title compound as a brown foam. (HPLC: t_(R) 3.61 min (Method A); M+H=530, 532 MS-ES).

Example 211.1 1-[1-(2-Hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(5-methoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 103.1 using 3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 211.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.02 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00-8.96 (m, 1H), 8.19-8.09 (m, 3H), 8.03-7.97 (m, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 4.94 (t, 1H), 4.25-4.11 (m, 2H), 3.92 (s, 3H), 3.84-3.69 (m, 2H), 3.59 (s, 3H), 2.38 (s, 3H), 1.98 (s, 3H))

Stage 211.1.1 3-Methoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

The title compound was synthesized in a similar manner as described for Stage 84.1.1 using methanol as replacement for isopropanol to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.86 min (Method A); M+H=250 MS-ES).

The following example was synthesized in a similar manner as described for Example 211.1 using 3-ethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 85.1.1).

HPLC Name of the MS-ES t_(R) Example structure example (M + H) (min) 211.2

8-(5-Ethoxy-6-methyl- pyridin-3-yl)-1-[1-(2- hydroxy-ethyl)-3- methyl-1H-pyrazol-4- yl]-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 459 2.14

Example 212.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and (R)-1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-pyrrolidin-3-ol (stage 212.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.03 min (Method A); M+H=456 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.25-8.22 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.57-7.53 (m, 1H), 7.43-7.41 (m, 1H), 6.55-6.51 (m, 1H), 4.95 (d, 1H), 4.42-4.36 (m, 1H), 3.92 (s, 3H), 3.56 (s, 3H), 3.54-3.43 (m, 3H), 3.37-3.31 (m, 1H), 2.08-1.86 (m, 2H), 1.96 (s, 3H))

Stage 212.1.1 (R)-1-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-pyrrolidin-3-ol

The title compound was synthesized in a similar manner as described for Stage 5.1.1-2 using (R)-3-hydroxypyrrolidine (Fluka, Buchs, Switzerland) to give the title compound as a crude black oil. (degrading under the HPLC condition: t_(R) 1.54 min (Method A); M+H=291 MS-ES).

The following example was synthesized in a similar manner as described for Example 212.1 using (S)-3-hydroxypyrrolidine (Fluka, Buchs, Switzerland).

HPLC Name of the MS-ES t_(R) Example structure example (M + H) (min) 212.2

1-(1,3-Dimethyl- 1H-pyrazol-4-yl)-8- [6-((S)-3-hydroxy- pyrrolidin-1-yl)- pyridin-3-yl]-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 456 2.04

Example 213.1 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((R)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 104 using 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 212.1, 0.116 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.20 min (Method A); M+H=470 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.26-8.23 (m, 1H), 8.12 (s, 1H), 8.05-8.02 (m, 1H), 7.88-7.84 (m, 1H), 7.59-7.55 (m, 1H), 7.44-7.41 (m, 1H), 6.59-6.54 (m, 1H), 4.08 (qt, 1H), 3.93 (s, 3H), 3.57 (s, 3H), 3.56-3.49 (m, 4H), 3.45-3.34 (m, 1H), 3.27 (s, 3H), 2.11-2.02 (m, 2H), 1.97 (s, 3H))

The following example was synthesized in a similar manner as described for Example 213.1 using (S)-3-hydroxypyrrolidine (Fluka, Buchs, Switzerland).

HPLC Name of the MS-ES t_(R) Example structure example (M + H) (min) 213.2

1-(1,3-Dimethyl- 1H-pyrazol-4-yl)- 8-[6-((S)-3- methoxy- pyrrolidin-1-yl)- pyridin-3-yl]-3- methyl-1,3- dihydro- imidazo[4,5- c]quinolin-2-one 470 2.19

Example 214 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and (tetrahydro-pyran-4-yl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (stage 214.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.13 min (Method A); M+H=470 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.89 (s, 1H), 8.15-8.10 (m, 2H), 8.04-8.00 (m, 1H), 7.84-7.79 (m, 1H), 7.47-7.42 (m, 1H), 7.41-7.38 (m, 1H), 6.78-6.73 (m, 1H), 6.57-6.53 (m, 1H), 4.00-3.82 (m, 3H), 3.91 (s, 3H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 1.96 (s, 3H), 1.91-1.83 (m, 2H), 1.49-1.37 (m, 2H))

Stage 214.1.1 (Tetrahydro-pyran-4-yl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1-2 using 4-aminotetrahydropyran (Maybridge, Basel, Switzerland) to give the title compound as a crude brown sticky solid. (degrading under the HPLC condition: t_(R) 1.74 min (Method A); M+H=305 MS-ES).

Example 215.1 8-[5-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propan-2-ol (Stage 215.1.1) to give the title compound as a white foam. (HPLC: t_(R) 2.13 min (Method A); M+H=457 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.69-8.66 (m, 1H), 8.46-8.44 (m, 1H), 8.21 (s, 1H), 8.16-8.12 (m, 1H), 7.98-7.91 (m, 2H), 7.58-7.56 (m, 1H), 5.26 (s, 1H), 4.53 (hp, 1H), 3.59 (s, 3H), 1.97 (s, 3H), 1.49 (s, 6H), 1.44 (d, 6H))

Stage 215.1.1 2-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propan-2-ol

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-(5-bromo-pyridin-3-yl)-propan-2-ol (stage 215.1.2, 1.518 mmol) to give the title compound as a crude black sticky oil. (degrading under the HPLC condition: t_(R) 1.87, 3.68 min (Method A); M+H=264 MS-ES).

Stage 215.1.2 2-(5-Bromo-pyridin-3-yl)-propan-2-ol

To a solution of 3,5-dibromopyridine (Aldrich, Buchs, Switzerland, 4.6 mmol) in dry THF under Ar was added slowly a ˜2 M solution of isopropylmagnesium chloride in THF (2.76 ml). The RM was stirred for 2 h at rt then was added acetone (6.9 mmol) and the RM was stirred for 2 h at rt. The RM was quenched with brine and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 70%). The fractions containing product were evaporated together to give the title compound as an oil. (HPLC: t_(R) 1.82 min (Method A); M+H=216, 218 MS-ES)

The following examples were synthesized in a similar manner as described for Example 215.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 215.2 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-[5-(1- hydroxy-1-methyl- ethyl)-pyridin-3-yl]-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 429 1.98 215.3 K

1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-8-[5-(1-hydroxy-1- methyl-ethyl)-pyridin- 3-yl]-3-methyl-1,3- dihydroimidazo[4,5- c]quinolin-2-one 459 2.16 215.4 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-8- [5-(1-hydroxy-1- methyl-ethyl)-pyridin- 3-yl]-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 443 2.05

Example 216 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-ethyl-1-hydroxy-propyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 215.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-pentanone (Fluka, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 2.13 min (Method A); M+H=457 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.63-8.57 (m, 2H), 8.16-8.11 (m, 2H), 8.01-7.96 (m, 1H), 7.76-7.73 (m, 1H), 7.65-7.62 (m, 1H), 4.82 (s, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.87-1.72 (m, 4H), 0.72-0.65 (m, 6H))

Example 217 (rac)-1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and acetaldehyde (Fluka, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 1.95 min (Method A); M+H=415 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.63-8.60 (m, 1H), 8.56-8.53 (m, 1H), 8.16-8.11 (m, 2H), 8.00-7.95 (m, 1H), 7.81-7.76 (m, 1H), 7.61-7.58 (m, 1H), 5.42-5.38 (m, 1H), 4.88-4.80 (m, 1H), 3.94-3.90 (m, 3H), 3.58 (s, 3H), 1.97-1.92 (m, 3H), 1.43-1.39 (m, 3H))

Example 218 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-cyclopentyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and cyclopentanone (Fluka, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 2.14 min (Method A); M+H=455 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.71-8.68 (m, 1H), 8.61-8.58 (m, 1H), 8.16-8.11 (m, 2H), 8.01-7.96 (m, 1H), 7.85-7.81 (m, 1H), 7.63-7.59 (m, 1H), 5.05 (s, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 1.98-1.77 (m, 8H), 1.95 (s, 3H))

Example 219 8-[5-(2-Fluoro-1-fluoromethyl-1-hydroxy-ethyl)-pyridin-3-yl]-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 215.1 using 1,3-difluoropropanone (Apollo Scientific, Cheshire, United Kingdom) to give the title compound as a yellow solid. (HPLC: t_(R) 2.24 min (Method A); M+H=493 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.72-8.70 (m, 1H), 8.55-8.52 (m, 1H), 8.22 (s, 1H), 8.18-8.14 (m, 1H), 8.09-8.07 (m, 1H), 7.96-7.92 (m, 1H), 7.59-7.57 (m, 1H), 6.31 (s, 1H), 4.78-4.70 (m, 2H), 4.66-4.58 (m, 2H), 4.54 (hp, 1H), 3.59 (s, 3H), 1.97 (s, 3H), 1.47-1.42 (m, 6H))

Example 220.1 2-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionitrile

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionitrile (Stage 220.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.36 min (Method A); M+H=438 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.78-8.76 (m, 1H), 8.73-8.71 (m, 1H), 8.18-8.14 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.93-7.90 (m, 1H), 7.62-7.60 (m, 1H), 3.88 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.80 (s, 3H), 1.79 (s, 3H))

Stage 220.1.1 2-Methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionitrile

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-(5-bromo-pyridin-3-yl)-2-methyl-propionitrile (stage 220.1.2, 1.111 mmol) to give the title compound as a crude brown soft solid. (degrading under the HPLC condition (Method A); M+H=273 MS-ES).

Stage 220.1.2 2-(5-Bromo-pyridin-3-yl)-2-methyl-propionitrile

To a solution of (5-bromo-pyridin-3-yl)-acetonitrile (Stage 220.1.3, 4.61 mmol) in dry DMF (15 ml) cooled with an ice-bath was added portionwise 55% sodium hydride in oil (9.97 mmol). Was then added iodomethane (13.56 mmol) and DMF (5 ml). The RM was stirred for 3 h at 0° C. then was quenched with saturated aqueous NH₄Cl, diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography (heptane/EtOAc 25%). The fractions containing product were evaporated together to give the title compound as an oil. (HPLC: t_(R) 2.72 min (Method A); M+H=225, 227 MS-ES)

Stage 220.1.3 (5-Bromo-pyridin-3-yl)-acetonitrile

To SOCl₂ (26.7 ml) cooled with an ice-bath was added portionwise (5-bromo-pyridin-3-yl)-methanol (ABCR, Karlsruhe, Germany, 26.6 mmol). The RM was refluxed for 1 h then was cooled at 0° C. and quenched with diethyl ether. The resulting precipitate was filtered, washed with cooled diethyl ether and dried under vacuum at 50° C. The solid was mixed with potassium cyanide (64.5 mmol), MeOH (35 ml) and water (14 ml) and the RM was refluxed for 2 h. The RM was cooled, quenched with aqueous K₂CO₃ and extracted with diethyl ether (3×). The combined organic layers dried over Na₂SO₄, filtered and evaporated to give the title compound as a purple solid. (HPLC: t_(R) 2.16 min (Method A); M+H=197, 199 MS-ES)

The following examples were synthesized in a similar manner as described for Example 220.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 220.2 F

2-{5-[1-(1-Ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-2-oxo- 2,3-dihydro-1H- imidazo[4,5- c]quinolin-8-yl]- pyridin-3-yl}-2- methyl-propionitrile 452 2.45 220.3 K

2-{5-[1-(3-Chloro-1- methyl-1H-pyrazol-4- yl)-3-methyl-2-oxo- 2,3-dihydro-1H- imidazo[4,5- c]quinolin-8-yl]- pyridin-3-yl}-2- methyl-propionitrile 458 2.55

Example 221.1 1-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-cyclobutanecarbonitrile

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-cyclobutanecarbonitrile (Stage 221.1.1) to give the title compound as an off-white foam. (HPLC: t_(R) 2.43 min (Method A); M+H=450 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01 (s, 1H), 8.74-8.73 (m, 1H), 8.70-8.68 (m, 1H), 8.17-8.12 (m, 2H), 8.06-8.03 (m, 1H), 7.90-7.88 (m, 1H), 7.63-7.61 (m, 1H), 3.89 (s, 3H), 3.59 (s, 3H), 2.86-2.71 (m, 4H), 2.13-2.01 (m, 2H), 1.97 (s, 3H))

Stage 221.1.1 1-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-cyclobutanecarbonitrile

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 1-(5-bromo-pyridin-3-yl)-cyclobutanecarbonitrile (stage 221.1.2, 0.476 mmol) to give the title compound as a crude back oil. (degrading under the HPLC condition: t_(R) 2.69 min (Method A); M+H=285 MS-ES).

Stage 221.1.2 1-(5-Bromo-pyridin-3-yl)-cyclobutanecarbonitrile

To a solution of (5-bromo-pyridin-3-yl)-acetonitrile (Stage 220.1.3, 1.37 mmol) in dry DMF (10 ml) was added 55% sodium hydride in oil (1.507 mmol). After 30 min stirring at rt was added 1-bromo-3-chloropropane (1.507 mmol). The RM was stirred for 1 h at rt then was added 55% sodium hydride in oil (1.507 mmol). The RM was stirred for 1 h at rt then quenched with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine (2×), dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing product were basified with NaHCO₃, concentrated and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a red oil. (HPLC: t_(R) 2.86 min (Method A); M+H=237, 239 MS-ES)

The following example was synthesized in a similar manner as described for Example 221.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 221.2 F

1-{5-[1-(1-Ethyl-3- methyl-1H-pyrazol-4- yl)-3-methyl-2-oxo-2,3- dihydro-1H- imidazo[4,5-c]quinolin- 8-yl]-pyridin-3-yl}- cyclobutanecarbonitrile 464 2.52

Example 222 N-{2-Chloro-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 222.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.33 min (Method A); M+H=462 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.80 (s, 1H), 9.01 (s, 1H), 8.34-8.28 (m, 2H), 8.17-8.11 (m, 2H), 7.95-7.90 (m, 1H), 7.61-7.58 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 2.18 (s, 3H), 1.93 (s, 3H))

Stage 222.1.1 N-[2-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using N-(5-bromo-2-chloro-pyridin-3-yl)-acetamide (stage 222.1.2, 2.434 mmol) to give the title compound as a crude back oil. (degrading under the HPLC condition: t_(R) 1.71 min (Method A); M+H=297 MS-ES).

Stage 222.1.2 N-(5-Bromo-2-chloro-pyridin-3-yl)-acetamide

To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) and triethylamine (1 ml) in dichloromethane (20 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.312 ml). The RM was stirred for 17 h at rt then was added acetyl chloride (0.3 ml), the RM was stirred for 3 h at rt. Acetyl chloride (0.1 ml) was added and the RM was stirred for 1 h at rt. The RM was quenched with aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: t_(R) 2.46 min (Method A); M+H=249, 251 MS-ES)

Example 223 N-{2-Chloro-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-methanesulfonamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-[2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 223.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.31 min (Method A); M+H=498 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.87 (s, 1H), 9.01 (s, 1H), 8.41-8.38 (m, 1H), 8.18-8.11 (m, 2H), 7.98-7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62-7.59 (m, 1H), 3.92 (s, 3H), 3.59 (s, 3H), 3.18 (s, 3H), 1.95 (s, 3H))

Stage 223.1.1 N-[2-Chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using N-(5-bromo-2-chloro-pyridin-3-yl)-methanesulfonamide (stage 223.1.2, 3.56 mmol) to give the title compound as a crude back oil. (degrading under the HPLC condition: t_(R) 2.05 min (Method A); M+H=333 MS-ES).

Stage 223.1.2 N-(5-Bromo-2-chloro-pyridin-3-yl)-methanesulfonamide

To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) in pyridine (7 ml) was added methanesulfonyl chloride (Fluka, Buchs, Switzerland, 0.365 ml). The RM was stirred for 22 h at rt then was added methanesulfonyl chloride (0.2 ml), the RM was stirred for 5 h at rt. Methanesulfonyl chloride (0.2 ml) was added and the RM was stirred for 17 h at it. The RM was evaporated to dryness and then taken in EtOAc, washed with aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a pink solid. (HPLC: t_(R) 2.91 min (Method A); M+H=285, 287 MS-ES)

Example 224.1 2-Amino-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-nicotinamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-amino-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (Stage 224.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.01 min (Method A); M+H=443 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.54 (q, 1H), 8.14-8.11 (m, 2H), 8.10-8.06 (m, 2H), 7.96-7.92 (m, 1H), 7.47-7.44 (m, 1H), 7.27 (s, br, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 2.78 (d, 3H), 1.95 (s, 3H))

Stage 224.1.1 2-Amino-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-amino-5-bromo-N-methyl-nicotinamide (stage 224.1.2, 0.352 mmol) to give the title compound as a crude brown oil. (degrading under the HPLC condition: t_(R) 1.46 min (Method A); M+H=278 MS-ES).

Stage 224.1.2 2-Amino-5-bromo-N-methyl-nicotinamide

To a solution of 2-amino-5-bromonicotinic acid (Combi-Blocks, San Diego, USA, 1.355 mmol) and triethylamine (0.378 ml) in dichloromethane (10 ml) cooled with an ice-bath was added a solution of trichloromethyl chloroformate (Acros, Basel, Switzerland, 0.677 mmol) in dichloromethane (10 ml). After 40 min stirring at 0° C., was added a solution 8 M of methylamine in EtOH (1.7 ml). The RM was stirred for 30 min at rt then was diluted with dichlromethane, washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: t_(R) 1.69 min (Method A); M+H=230, 232 MS-ES)

The following example was synthesized in a similar manner as described for Example 224.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 224.2 G

2-Amino-5-[1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-2-oxo-2,3- dihydro-1H- imidazo[4,5- c]quinolin-8-yl]-N- methyl-nicotinamide 471 2.12

Example 225 2-Amino-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-isopropyl-nicotinamide

The title compound was synthesized in a similar manner as described for Example 224 using isopropylamine (Aldrich, Buchs, Switzerland) as replacement for methylamine to give the title compound as an off-white solid. (HPLC: t_(R) 2.20 min (Method A); M+H=471 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.30 (d, 1H), 8.13-8.04 (s, 4H), 7.97-7.92 (m, 1H), 7.45-7.42 (m, 1H), 7.21 (s, br, 2H), 4.08 (oc, 1H), 3.88 (s, 3H), 3.57 (s, 3H), 1.97 (s, 3H), 1.22-1.15 (m, 6H))

Example 226 2-Amino-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-(2-methoxy-ethyl)-nicotinamide

The title compound was synthesized in a similar manner as described for Example 224 using 2-methoxyethylamine (Fluka, Buchs, Switzerland) as replacement for methylamine to give the title compound as a white solid. (HPLC: t_(R) 2.10 min (Method A); M+H=487 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.65 (t, 1H), 8.15-8.06 (m, 4H), 7.97-7.93 (m, 1H), 7.47-7.44 (m, 1H), 7.27 (s, br, 2H), 3.89 (s, 3H), 3.57 (s, 3H), 3.50-3.34 (m, 4H), 3.26 (s, 3H), 1.96 (s, 3H))

Example 227 2-Amino-N-ethyl-5-[1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-nicotinamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-amino-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (stage 227.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.22 min (Method A); M+H=485 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.93 (s, 1H), 8.53 (t, 1H), 8.19 (s, 1H), 8.11-8.06 (m, 3H), 7.95-7.91 (m, 1H), 7.44-7.41 (m, 1H), 7.22 (s, br, 2H), 4.52 (hp, 1H), 3.57 (s, 3H), 3.35-3.18 (m, 2H), 1.96 (s, 3H), 1.47-1.42 (m, 6H), 1.14 (t, 3H))

Stage 227.1.1 2-Amino-N-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide

The title compound was synthesized in a similar manner as described for Stage 224.1.1 using 2 Methylamine in MeOH (Aldrich, Buchs, Switzerland) as replacement for the methylamine to give the title compound as a crude brown sticky oil. (degrading under the HPLC condition: t_(R) 1.69 min (Method A); M+H=292 MS-ES).

Example 228 2-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 228.1.1) to give the title compound as an off-white foam. (HPLC: t_(R) 1.97 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.55-8.53 (m, 1H), 8.45-8.43 (m, 1H), 8.16-8.12 (m, 2H), 8.07-8.01 (m, 1H), 7.95-7.90 (m, 1H), 7.77-7.74 (m, 1H), 7.59-7.57 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.51 (s, 2H), 2.60 (d, 3H), 1.95 (s, 3H))

Stage 228.1.1 N-Methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-(5-bromo-pyridin-3-yl)-N-methyl-acetamide (stage 228.1.2, 0.851 mmol) to give the title compound as a crude black oil. (degrading under the HPLC condition (Method A); M+H=277 MS-ES).

Stage 228.1.2 2-(5-Bromo-pyridin-3-yl)-N-methyl-acetamide

The title compound was synthesized in a similar manner as described for Example 103 using (5-bromo-pyridin-3-yl)-acetic acid (ABCR, Karlsruhe, Germany, 1.815 mmol) and 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 7.26 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 1.74 min (Method A); M+H=229, 231 MS-ES)

Example 229 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-hydroxy-1,1-dim ethyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a solution of 2-{5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionic acid methyl ester (Stage 229.1.1, 0.134 mmol) in THF (1.2 ml) were added MeOH (0.009 ml) and NaBH₄ (0.185 mmol) four times during the course of the heating at 40° C. for 39 h. After that, the RM was quenched with saturated aqueous NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a white foam. (HPLC: t_(R) 2.06 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.62-8.58 (m, 2H), 8.15-8.11 (m, 2H), 8.01-7.96 (m, 1H), 7.74-7.71 (m, 1H), 7.62-7.59 (m, 1H), 4.79 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 3.50 (d, 2H), 1.96 (s, 3H), 1.30 (s, 6H))

Stage 229.1.1 2-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionic acid methyl ester

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.215 mmol) and 2-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionic acid methyl ester (Stage 229.1.1, 0.279 mmol) to give the title compound as a brown solid. (HPLC: t_(R) 2.28 min (Method A); M+H=471 MS-ES)

Stage 229.1.2 2-Methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionic acid methyl ester

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 2-(5-bromo-pyridin-3-yl)-2-methyl-propionic acid methyl ester (stage 229.1.2, 0.872 mmol) to give the title compound as a crude black sticky solid. (degrading under the HPLC condition: t_(R) 2.20 min (Method A); M+H=306 MS-ES).

Stage 229.1.3 2-(5-Bromo-pyridin-3-yl)-2-methyl-propionic acid methyl ester

The title compound was synthesized in a similar manner as described for stage 220.1.2 using (5-bromo-pyridin-3-yl)-acetic acid methyl ester (stage 229.1.4, 1.815 mmol) to give the title compound as yellowish oil. (HPLC: t_(R) 2.74 min (Method A); M+H=258, 260 MS-ES)

Stage 229.1.4 (5-Bromo-pyridin-3-yl)-acetic acid methyl ester

A mixture of (5-bromo-pyridin-3-yl)-acetic acid (ABCR, Karlsruhe, Germany, 4.54 mmol) and concentrated sulfuric acid (0.02 ml) in MeOH was reluxed for 13.5 h. The RM was concentrated, taken in EtOAc and sonicated. The organic layer was washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as a brown oil. (HPLC: t_(R) 2.21 min (Method A); M+H=230, 232 MS-ES)

Example 230 8-(5-Aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(N-boc-aminomethyl)pyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as an off-white solid. (HPLC: t_(R) 1.87 min (Method A); M+H=400 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.51 (m, 2H), 8.17-8.11 (m, 2H), 7.99-7.95 (m, 1H), 7.86-7.83 (m, 1H), 7.61-7.58 (m, 1H), 3.92 (s, 3H), 3.79 (s, 2H), 3.58 (s, 3H), 2.06-1.97 (br, 2H), 1.95 (s, 3H))

Example 231 N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-ylmethyl}-acetamide

To a mixture of 8-(5-aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 230, 0.053 mmol) and Hünig's base (0.014 ml) in dichloromethane (1 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.058 mmol). The RM was stirred for 45 min at rt then evaporated to dryness. The residue was taken in MeOH and purified by preparative HPLC. The fractions containing product were basified with NaHCO₃, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: t_(R) 1.95 min (Method A); M+H=442 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.53 (m, 1H), 8.48-8.46 (m, 1H), 8.40 (t, 1H), 8.16-8.12 (m, 2H), 7.94-7.90 (m, 1H), 7.78-7.75 (m, 1H), 7.58-7.56 (m, 1H), 4.38-4.27 (m, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H), 1.89 (s, 3H))

Example 232 8-(5-Aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 231 using methansulfonyl chloride (Aldrich, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: t_(R) 1.98 min (Method A); M+H=478 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.01-8.99 (m, 1H), 8.58-8.55 (m, 2H), 8.17-8.13 (m, 2H), 7.95-7.91 (m, 2H), 7.65-7.58 (m, 2H), 4.26 (s, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 2.96 (s, 3H), 1.95 (s, 3H))

Example 233 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1,3,3-trimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Stage 233.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.53 min (Method A); M+H=468 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.96 (s, 1H), 8.32-8.29 (m, 1H), 8.14-8.09 (m, 2H), 7.96-7.91 (m, 1H), 7.79-7.76 (m, 1H), 7.54-7.51 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.18 (s, 3H), 1.96 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H))

Stage 233.1.1 1,3,3-Trimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using 5-bromo-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (stage 233.1.2, 0.779 mmol) to give the title compound as a crude black solid. (degrading under the HPLC condition: t_(R) 2.05 min (Method A); M+H=303 MS-ES).

Stage 233.1.2 5-Bromo-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one

To a mixture of 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Aldrich, Buchs, Switzerland, 1.394 min) in DMF (7 ml) cooled with an ice-bath was added 55% NaH in oil (1.6 mmol) and the RM was stirred for 30 min at rt, then was added iodomethane (0.1 ml) and the RM was stirred for 30 min at rt. The RM was cooled with an ice-bath and was added 55% NaH in oil (1.6 mmol) and the RM was stirred for 15 min at rt, then was added iodomethane (0.1 ml) and the RM was stirred for 30 min at rt. The RM was cooled with an ice-bath and was added 55% NaH in oil (1.6 mmol) and the RM was stirred for 15 min at rt, then was added iodomethane (0.1 ml) and the RM was stirred for 1.5 h at rt. The RM was quenched with saturated aqueous NaHCO₃ and extracted with EtOAc. The organic layer was washed with brine (3×), dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: t_(R) 2.99 min (Method A); M+H=255, 257 MS-ES)

Example 234.1 8-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F, 0.101 mmol) and 2,4-dimethoxypyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA, 0.119 mmol) to give the title compound as a white foam. (HPLC: t_(R) 2.51 min (Method A); M+H=446 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.97 (s, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 8.07-8.04 (m, 1H), 7.78-7.74 (m, 1H), 7.56-7.54 (m, 1H), 4.14 (q, 2H), 3.92 (s, 1H), 3.92 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.33 (t, 3H))

The following examples were synthesized in a similar manner as described for Example 234.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 234.2 A

8-(2,4-Dimethoxy- pyrimidin-5-yl)-1-(1,3- dimethyl-1H-pyrazol- 4-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 432 2.43 234.3 G

8-(2,4-Dimethoxy- pyrimidin-5-yl)-1-(1- isopropyl-3-methyl- 1H-pyrazol-4-yl)-3- methyl-1,3-dihydro- imidazo[4,5- c]quinolin-2-one 460 2.62 234.4 C

8-(2,4-Dimethoxy- pyrimidin-5-yl)-1-(2,5- dimethyl-2H-pyrazol- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 432 2.56

Example 235 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-ethylamino-4-methoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and ethyl-[4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine (Stage 235.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.24 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.16-8.06 (m, 3H), 8.01-7.97 (m, 1H), 7.74-7.69 (m, 1H), 7.61-7.58 (m, 1H), 3.88 (s, 3H), 3.84 (s, br, 3H), 3.56 (s, 3H), 3.36-3.28 (m, 2H), 1.93 (s, 3H), 1.13 (t, 3H))

Stage 235.1.1 Ethyl-[4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-amine

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using (5-bromo-4-methoxy-pyrimidin-2-yl)-ethyl-amine (stage 235.1.2, 0.366 mmol) to give the title compound as a crude back oil. (degrading under the HPLC condition: t_(R) 1.91 min (Method A); M+H=280 MS-ES).

Stage 235.1.2 (5-Bromo-4-methoxy-pyrimidin-2-yl)-ethyl-amine

To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (Frontier Scientific, Logan, USA, 0.895 mmol) in THF (2.5 ml) cooled with an ice-bath was added a 2 M solution of ethylamine in MeOH (Aldrich, Buchs, Switzerland, 0.492 ml). The RM was stirred at 0° C. for 1 h and at rt for 66 h then the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO₃, with brine, dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH₂Cl₂/iPrOH 0% to 6%) to give after evaporation of the fractions containing the title compound an off-white solid. (HPLC: t_(R) 2.16 min (Method A); M+H=232, 234 MS-ES)

Example 236 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(4-methoxy-2-methylamino-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate F) and [4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine (stage 236.1.1) to give the title compound as a white solid. (HPLC: t_(R) 2.19 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.91 (s, 1H), 8.11 (s, 1H), 8.08-8.02 (m, 1H), 8.01-7.97 (m, 1H), 7.74-7.69 (m, 1H), 7.50-7.48 (m, 1H), 7.27-7.16 (m, 1H), 4.15 (q, 2H), 3.85 (s, br, 3H), 3.56 (s, 3H), 2.82 (d, 3H), 1.95 (s, 3H) 1.36 (t, 3H))

Stage 236.1.1 [4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine

The title compound was synthesized in a similar manner as described for Stage 235.1.1 using 8 M methylamine in EtOH (Fluka, Buchs, Switzerland, 0.366 mmol) to give the title compound as a crude back oil. (degrading under the HPLC condition: t_(R) 1.69 min (Method A); M+H=266 MS-ES).

Example 237 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

A mixture of acetic acid 3-(tert-butoxycarbonyl-ethyl-amino)-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-2-ylmethyl ester (stage 155.1.1, 0.107 mmol) and KCN (0.16 mmol) in EtOH (0.6 ml) was stirred for 17 h at 80° C. The RM was diluted with EtOAc and washed with water, with brine, dried over Na₂SO₄, filtered and evaporated. The residue The residue was absorbed on silica gel and purified by flash chromatography (CH₂Cl₂/MeOH 0% to 8%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: t_(R) 2.42 min (Method A); M+H=470 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.35-8.32 (m, 1H), 8.17-8.13 (m, 1H), 8.11 (s, 1H), 8.04-8.00 (m, 1H), 7.62-7.59 (m, 1H), 7.49-7.47 (m, 1H), 5.40-5.31 (m, 2H), 4.04-3.85 (m, 2H), 3.87 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H), 1.24 (t, 3H))

Example 238 8-(5-Chloro-6-hydroxymethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 169.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and acetic acid 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester (Stage 238.1.1) to give the title compound as an off-white solid. (HPLC: t_(R) 2.27 min (Method A); M+H=435 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.00 (s, 1H), 8.65-8.62 (m, 1H), 8.18-8.11 (m, 2H), 8.05-8.00 (m, 1H), 7.97-7.94 (m, 1H), 7.58-7.55 (m, 1H), 5.30 (t, 1H), 4.67 (d, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H))

Stage 238.1.1 Acetic acid 3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylmethyl ester

The title compound was synthesized in a similar manner as described for Stage 5.1.1 using acetic acid 5-bromo-3-chloro-pyridin-2-ylmethyl ester (stage 238.1.2, 0.306 mmol) to give the title compound as a crude back oil. (degrading under the HPLC condition: t_(R) 2.65 min (Method A); M+H=312 MS-ES).

Stage 238.1.2 Acetic acid 5-bromo-3-chloro-pyridin-2-ylmethyl ester

The title compound was synthesized in a similar manner as described for Stage 194.1.2 using (5-bromo-3-chloro-pyridin-2-yl)-methanol (stage 238.1.3, 0.351 mmol) to give the title compound as an oil. (HPLC: t_(R) 3.04 min (Method A); M+H=264 (BrCl pattern) MS-ES)

Stage 238.1.3 (5-Bromo-3-chloro-pyridin-2-yl)-methanol

The title compound was synthesized in a similar manner as described for Stage 190.1.2-3 using 5-bromo-3-chloro-2-methyl-pyridine (stage 238.1.4, 0.801 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.40 min (Method A); M+H=222, 244 MS-ES)

Stage 238.1.4 5-Bromo-3-chloro-2-methyl-pyridine

The title compound was synthesized in a similar manner as described for Stage 75.1.5 using 5-bromo-2,3-dichloropyridine (Asymchem Laboratories, Morrisville, N.C., USA, 2.182 mmol) to give the title compound as a crude black solid. (HPLC: t_(R) 3.29 min (Method A); M+H=206, 208 MS-ES)

Example 239 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-methoxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 104 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 215.2, 0.121 mmol) to give the title compound as a film. (HPLC: t_(R) 2.19 min (Method A); M+H=443 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.71-8.68 (m, 1H), 8.62-8.59 (m, 1H), 8.16-8.11 (m, 2H), 8.04-7.99 (m, 1H), 7.76-7.73 (m, 1H), 7.63-7.60 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.05 (s, 3H), 1.97 (s, 3H), 1.54 (s, 6H))

Example 240 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-ethoxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 104 using 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 215.2, 0.063 mmol) and iodethane as replacement for the iodomethane to give the title compound as a film. (HPLC: t_(R) 2.30 min (Method A); M+H=457 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.69-8.67 (m, 1H), 8.63-8.61 (m, 1H), 8.16-8.12 (m, 2H), 8.03-7.98 (m, 1H), 7.77-7.74 (m, 1H), 7.63-7.61 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.21 (q, 2H), 1.97 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H), 1.09 (t, 3H))

Example 241 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-(methylamino)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-thione

The title compound was synthesized in a similar manner as described for Example 128.1 using 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 118.1, 0.051 mmol) to give the title compound as a white solid. (HPLC: t_(R) 2.44 min (Method A); M+H=444 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.11 (s, 1H), 8.21-8.17 (m, 2H), 8.12-8.08 (m, 1H), 7.95-7.90 (m, 1H), 7.49-7.44 (m, 1H), 7.39-7.36 (m, 1H), 6.75 (q, 1H), 6.50-6.45 (m, 1H), 4.58 (hp, 1H), 3.94 (s, 3H), 2.79 (d, 3H), 1.93 (s, 3H), 1.52-1.46 (m, 6H))

Example 242.1 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-ethyl-2-methylamino-nicotinamide

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-ethyl-2-methylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (Stage 242.1.1) to give the title compound as a yellowish foam. (HPLC: t_(R) 2.17 min (Method A); M+H=471 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.58 (t, 1H), 8.25-8.20 (m, 2H), 8.11-8.06 (m, 2H), 8.05-8.02 (m, 1H), 7.96-7.92 (m, 1H), 7.47-7.44 (m, 1H), 3.89 (s, 3H), 3.57 (s, 3H), 3.40-3.19 (m, 2H), 2.93 (d, 3H), 1.97 (s, 3H), 1.15 (t, 3H))

Stage 242.1.1 N-Ethyl-2-methylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide

The title compound was synthesized in a similar manner as described for Stage 227.1.1 using 5-bromo-2-methylamino-nicotinic acid (Princeton BioMolecular Research, Monmouth Junction, N.J., USA) to give the title compound as a crude brown oil. (degrading under the HPLC condition: t_(R) 1.81 min (Method A); M+H=306 MS-ES).

The following example was synthesized in a similar manner as described for Example 242.1 using the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 242.2 H

N-Ethyl-2- methylamino-5-[3- methyl-2-oxo-1-(1,3,5- trimethyl-1H-pyrazol- 4-yl)-2,3-dihydro-1H- imidazo[4,5- c]quinolin-8-yl]- nicotinamide 432 2.43

Example 243 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 190 using ethanol as replacement for isopropanol to give the title compound as a white solid. (HPLC: t_(R) 2.11 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.28-8.25 (m, 1H), 8.14-8.10 (m, 2H), 8.04-8.00 (m, 1H), 7.63-7.61 (m, 1H), 7.38-7.35 (m, 1H), 4.88 (t, 1H), 4.57 (d, 2H), 4.22-4.14 (m, 2H), 3.89 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.41 (t, 3H))

Example 244 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-hydroxymethyl-5-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 190 using 2-methoxyethanol as replacement for isopropanol to give the title compound as a white solid. (HPLC: t_(R) 2.09 min (Method A); M+H=475 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.25 (m, 1H), 8.15-8.11 (m, 2H), 8.04-8.00 (m, 1H), 7.63-7.60 (m, 1H), 7.44-7.41 (m, 1H), 4.87 (t, 1H), 4.57 (d, 2H), 4.31-4.22 (m, 2H), 3.89 (s, 3H), 3.75 (t, 2H), 3.58 (s, 3H), 3.35 (s, 3H), 1.97 (s, 3H))

Example 245 8-(5-Amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (stage 245.1.1) and 3-aminopyridine-5-boronic acid pinacol ester (Apollo Scientific, Cheshire, United Kingdom) to give the title compound as a white solid. (HPLC: t_(R) 2.02 min (Method A); M+H=400 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.02 (s, 1H), 8.15 (s, 1H), 8.12-8.07 (m, 1H), 7.94-7.91 (m, 1H), 7.81-7.76 (m, 2H), 7.54-7.51 (m, 1H), 7.03-7.00 (m, 1H), 5.44 (s, 2H), 4.11 (q, 2H), 3.91 (s, 3H), 1.94 (s, 3H), 1.35 (t, 3H))

Stage 245.1.1 8-Bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

To a solution of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 0.698 mmol) in DMF (5 ml) cooled with an ice-bath was added 55% NaH in oil (1.398 mmol). The RM was stirred for 30 min at rt then was added iodoethane (0.085 ml) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc and washed with saturated aqueous NaHCO₃, with brine (2×), dried over Na₂SO₄, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH₂Cl₂/MeOH 0% to 3.5%). The fractions containing product were evaporated together to give the title compound as a brown solid. (HPLC: t_(R) 2.41 min (Method A); M+H=386, 388 MS-ES)

Example 246 3-Allyl-8-(5-amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 245 using allyl bromide (Fluka, Buchs, Switzerland) as replacement for iodoethane to give the title compound as a white solid. (HPLC: t_(R) 2.08 min (Method A); M+H=412 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.89 (s, 1H), 8.17 (s, 1H), 8.11-8.08 (m, 1H), 7.94-7.92 (m, 1H), 7.81-7.77 (m, 2H), 7.55-7.53 (m, 1H), 7.03-7.01 (m, 1H), 6.09-5.98 (m, 1H), 5.44 (s, 2H), 5.26-5.17 (m, 2H), 4.72 (d, 2H), 3.92 (s, 3H), 1.95 (s, 3H))

Example 247.1 N,N-Diethyl-2-{3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide

To a solution of {3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetic acid (Stage 247.1.1, 0.12 mmol) and DMF (0.007 ml) in dichloromethane (2 ml) was added oxallyl chloride (0.36 mmol) and the RM was stirred for 45 min at rt. The RM was quenched with diethylamine (Riedel-deHaën, Buchs, Switzerland, 2.4 mmol) and stirred for 5 min at rt then diluted with saturated aqueous NaHCO₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na₂SO₄, filtered and evaporated. The residue was taken in MeOH/DMF and purified by preparative HPLC. The fractions containing pure product were basified with NaHCO₃, concentrated, cooled at 4° C. and the precipitate was filtered, washed with water and dried under vacuum to give the title compound as white solid. (HPLC: t_(R) 2.63 min (Method A); M+H=540 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.92 (s, 1H), 8.57 (s, 2H), 8.07-8.04 (m, 2H), 7.87-7.84 (m, 1H), 7.67-7.65 (m, 1H), 5.21-5.04 (m, 2H), 3.57 (s, 3H), 3.52-3.46 (m, 4H), 3.42-3.34 (m, 2H), 3.32-3.34 (m, 2H), 1.96-1.90 (m, 4H), 1.94 (s, 3H), 1.18 (t, 3H), 0.99 (t, 3H))

Stage 247.1.1 {3-Methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetic acid

The title compound was synthesized in a similar manner as described for Example 1.1 using [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (stage 247.1.2) and 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a yellow hydrochloride salt after evaporation of the fractions containing pure product and exchange of the trifluoroacetate to the chlorure. (HPLC: t_(R) 2.29 min (Method A); M+H=485, M−H=483 MS-ES)

Stage 247.1.2 [4-(8-Bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester

The title compound was synthesized in a similar manner as described for Stage 245.1.1 using [4-(8-bromo-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (Stage 101.1.3, 3.43 mmol) and iodomethane to give the title compound as brown solid. (HPLC: t_(R) 2.42 min (Method A); M+H=430, 432 MS-ES)

The following examples were synthesized in a similar manner as described for Example 247.1 using the specified amines (Fluka, Buchs, Switzerland).

HPLC Name of the MS-ES t_(R) Example amine structure example (M + H) (min) 247.2 azetidine

1-[1-(2-Azetidin-1-yl- 2-oxo-ethyl)-3- methyl-1H-pyrazol-4- yl]-3-methyl-8-(2- pyrrolidin-1-yl- pyrimidin-5-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 524 2.48 247.3 Morpholine

3-Methyl-1-[3- methyl-1-(2- morpholin-4-yl-2- oxo-ethyl)-1H- pyrazol-4-yl]-8-(2- pyrrolidin-1-yl- pyrimidin-5-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 554 2.44 247.4 Pyrrolidine 7

3-Methyl-1-[3- methyl-1-(2-oxo-2- pyrrolidin-1-yl-ethyl)- 1H-pyrazol-4-yl)-8- (2-pyrrolidin-1-yl- pyrimidin-5-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 538 2.57 247.5 Morpholine

3-Methyl-1-{3- methyl-1-[2-(4- methyl-piperazin-1- yl)-2-oxo-ethyl]-1H- pyrazol-4-yl}-8-(2- pyrrolidin-1-yl- pyrimidin-5-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 567 2.26

Example 248.1 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-6-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one

The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and [3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (Stage 248.1.1) to give the title compound as a yellowish foam. (HPLC: t_(R) 2.24 min (Method A); M+H=472 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.90 (s, 1H), 8.20 (s, 1H), 8.15-8.13 (m, 1H), 8.05-8.02 (m, 1H), 7.85-7.81 (m, 1H), 7.48-7.45 (m, 1H), 7.43-7.41 (m, 1H), 6.13 (q, 1H), 4.55 (hp, 1H), 4.30 (s, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 2.86 (d, 3H), 1.96 (s, 3H), 1.49-1.45 (m, 6H))

Stage 248.1.1 [3-Methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine

The title compound was synthesized in a similar manner as described for Stage 168.1.1 using (5-bromo-2-methylamino-pyridin-3-yl)-methanol (stage 248.1.2) to give the title compound as a crude back oil. (degrading under the HPLC condition (Method A); M+H=279 MS-ES).

Stage 248.1.2 (5-Bromo-2-methylamino-pyridin-3-yl)-methanol

The title compound was synthesized in a similar manner as described for Example 171 using 6-bromo-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.3) to give the title compound as a solid. (HPLC: t_(R) 1.92 min (Method A); M+H=217, 219 MS-ES).

The following examples were synthesized in a similar manner as described for Example 1.1 using [3-methoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (Stage 248.1.1) and the specified intermediate.

HPLC Name of the MS-ES t_(R) Example Intermed. structure example (M + H) (min) 248.2 F

1-(1-Ethyl-3-methyl- 1H-pyrazol-4-yl)-8-(5- methoxymethyl-6- methylamino-pyridin- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 458 2.18 248.3 A

1-(1,3-Dimethyl-1H- pyrazol-4-yl)-8-(5- methoxymethyl-6- methylamino-pyridin- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 444 2.12 248.4 K

1-(3-Chloro-1-methyl- 1H-pyrazol-4-yl)-8-(5- methoxymethyl-6- methylaminopyridin- 3-yl)-3-methyl-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 464 2.27 248.5 H

8-(5-Methoxymethyl- 6-methylamino- pyridin-3-yl)-3-methyl- 1-(1,3,5-trimethyl-1H- pyrazol-4-yl)-1,3- dihydro-imidazo[4,5- c]quinolin-2-one 458 2.17

Example 249 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one

A mixture of 6-(3,4-dimethoxy-phenyl)-4-(1,3-dimethyl-1H-pyrazol-4-ylamino)-[1,5]naphthyridine-3-carboxylic acid ethyl ester (Stage 249.1.1, 160 mg, 0.358 mmol) and LiOH 1 M (0.715 ml, 0.715 mmol) in dioxane (2.6 ml) was stirred at 50° C. for 2.5 h. The RM was then quenched with 2 M aqueous HCl (0.36 ml, 0.072 mmol) and evaporated to dryness. The residue was diluted with toluene (2.6 ml) and NMP (1.3 ml) and treated under argon with TEA (0.164 ml) and diphenylphosphorylazide (0.231 ml). The RM was stirred again at 95° C. for 2.5 h. After that, the RM was quenched with saturated aqueous NaHCO₃, the suspension was then filtered. The cake was dissolved with EtOAc (200 ml) and THF (30 ml). The solution was extracted with brine (2×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as an off-white solid. (HPLC: t_(R) 2.56 min (Method A); M+H=417 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.80 (s, 1H), 8.75 (s, 1H), 8.38 (d, 1H), 8.22 (d, 1H), 7.96 (s, 1H), 7.60-7.55 (m, 1H), 7.42-7.38 (m, 1H), 7.02-6.98 (m, 1H), 3.83 (s, 6H), 3.81 (s, 3H), 1.97 (s, 3H))

Stage 249.1.1 6-(3,4-Dimethoxy-phenyl)-4-(1,3-dimethyl-1H-pyrazol-4-ylamino)-[1,5]naphthyridine-3-carboxylic acid ethyl ester

A mixture of 4-chloro-6-(3,4-dimethoxy-phenyl)-[1,5]naphthyridine-3-carboxylic acid ethyl ester (Stage 249.1.2, 170 mg, 0.456 mmol), 1,3-dimethyl-4-aminopyrazole.HCl (ChemCollect, Remscheid, Germany, 85 mg, 0.576 mmol) and 1,2,2,6,6-pentamethylpyridine (0.292 ml, 1.596 mmol) in DMA (2 ml) was stirred at 50° C. for 5.5 h. Then the RM was cooled to rt and quenched with water, before being extracted with EtOAc (2×). The combined organic layers were dried over Na₂SO₄, filtered and evaporated to dryness to give the title compound as an orange solid. (HPLC: t_(R) 2.93 min (Method A); M+H=448 MS-ES)

Stage 249.1.2 4-Chloro-6-(3,4-dimethoxy-phenyl)-[1,5]naphthyridine-3-carboxylic acid ethyl ester

A mixture of 6-(3,4-dimethoxy-phenyl)-4-hydroxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (Stage 249.1.3, 493 mg, 1.391 mmol) in POCl₃ was stirred at 125° C. for 1.5 h. Then the RM was evaporated to dryness. The residue was quenched with saturated aqueous NaHCO₃. The suspension was filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as a brown solid. Used for next step without further purification. (HPLC: t_(R) 3.80 min (Method A); M+H=373 MS-ES)

Stage 249.1.3 6-(3,4-Dimethoxy-phenyl)-4-hydroxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester

A mixture of 6-(3,4-dimethoxy-phenyl)-pyridin-3-ylamine (Stage 249.1.4, 2.0 g, 8.69 mmol) and diethyl ethoxymethylenemalonate (Aldrich, Buchs, Switzerland, 2.087 ml, 10.42 mmol) in o-xylene (22 ml) was heated by microwaves at 150° C. for 45 min and at 250° C. for 9 h. The RM was cooled to rt and crystallized with diethylether. The suspension was filtered and the cake was triturated again in hot EtOAc and cooled after in the freezer. The suspension was filtered again. The cake was washed with EtOAc and dried in the vacuum oven to give the title compound as a brown solid. Used for next step without further purification. (HPLC: t_(R) 2.58 min (Method A); M+H=355 MS-ES)

Stage 249.1.4 6-(3,4-dimethoxy-phenyl)-pyridin-3-ylamine

To a mixture of 2-(3,4-dimethoxyphenyl)-5-nitropyridine (Interchim, Montlucon, France, 2.85 g, 10.95 mmol) in MeOH (27 ml) and THF (27 ml), Ra/Ni catalyst (1.10 g, 10.95 mmol) was added and shaked under hydrogen at rt for 15 h. After that, the RM was filtered over celite, the catalyst was washed with MeOH and the filtrate was evaporated to dryness to give the title compound as an off-white solid. (HPLC: t_(R) 2.22 min (Method A); M+H=231 MS-ES)

Example 250 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one

A mixture of 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 249, 50 mg, 0.120 mmol) and NaH 55% (8 mg, 0.183 mmol) in DMF (1.2 ml) was stirred at rt for 20 min. Then iodomethane (0.011 ml, 0.180 mmol) was added and the RM was stirred at rt for 2.25 h. After that, the RM was quenched with saturated aqueous NaHCO₃, the suspension was then filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as an off-white solid. (HPLC: t_(R) 2.67 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.38 (d, 1H), 8.24 (d, 1H), 7.96 (s, 1H), 7.62-7.54 (m, 1H), 7.42-7.38 (m, 1H), 7.02 (d, 1H), 3.85 (s, 6H), 3.81 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))

Example 251 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one

A mixture of 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 249, 50 mg, 0.120 mmol) and NaH 55% (8 mg, 0.183 mmol) in DMF was stirred at rt for 25 min. Then iodoethane (0.015 ml, 0.186 mmol) was added and the RM was stirred at rt for 5.5 h. After that, the RM was quenched with saturated aqueous NaHCO₃, the suspension was then filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as a white solid. (HPLC: t_(R) 2.74 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.03 (s, 1H), 8.40-8.32 (m, 1H), 8.25-8.19 (m, 1H), 7.95 (s, 1H), 7.60-7.52 (m, 1H), 7.41-7.36 (m, 1H), 7.04-6.97 (m, 1H), 4.11 (q, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 1.94 (s, 3H), 1.37 (t, 3H))

Example 252 8-(3,4-Dimethoxy-phenyl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one

The title compound was synthesized in a similar manner as described for Example 249 using 2,5-dimethyl-2H-pyrazol-3-ylamine (Aldrich, Buchs, Switzerland, 130 mg, 1.170 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.73 min (Method A); M+H=417 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 11.96 (s, 1H), 8.79 (s, 1H), 8.38 (d, 1H), 8.25 (d, 1H), 7.62-7.56 (m, 1H), 7.42-7.38 (m, 1H), 7.02-6.97 (m, 1H), 6.26 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.58 (s, 3H), 2.23 (s, 3H))

Example 253 8-(3,4-Dimethoxy-phenyl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one

The title compound was synthesized in a similar manner as described for Example 250 using 8-(3,4-dimethoxy-phenyl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 252, 37 mg, 0.088 mmol) to give the title compound as an off-white solid. (HPLC: t_(R) 2.90 min (Method A); M+H=431 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 9.03 (s, 1H), 8.43-8.35 (m, 1H), 8.29-8.22 (m, 1H), 7.62-7.54 (m, 1H), 7.38 (s, 1H), 7.03-6.95 (m, 1H), 6.31-6.23 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.60 (s, 3H), 3.52 (s, 3H), 2.23 (s, 3H))

Example 254 8-(3,4-Dimethoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one

The title compound was synthesized in a similar manner as described for Example 250 using 1-ethyl-3-methyl-1H-pyrazol-4-ylamine.HCl (ChemCollect, Remscheid, Germany, 95 mg, 0.587 mmol) to give the title compound as a light yellow foam. (HPLC: t_(R) 2.74 min (Method A); M+H=445 MS-ES; ¹H-NMR (d₆-DMSO, 400 MHz) 8.98 (s, 1H), 8.41-8.32 (m, 1H), 8.25-8.18 (m, 1H), 7.95 (s, 1H), 7.56-7.49 (m, 1H), 7.46-7.39 (m, 1H), 7.02-6.94 (m, 1H), 4.18-4.07 (m, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.60 (s, 3H), 1.97 (s, 3H), 1.46-1.35 (m, 3H))

Physicochemical Properties

The physicochemical properties of relevance for the absorption of the compound, such as the solubility and the membrane permeability, especially at a pH close to neutral pH can be measured using the procedure as described by L. ZHOU et al. in JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 11, p. 3052-3071 (2007) for the solubility at pH 6.8 and the procedure as described by F. Wohnsland and B. Faller in Journal of Medicinal Chemistry Vol 44, p. 923-930 (2001) for the Parallel Artificial Membrane Permeability Assay (PAMPA) at pH 6.8.

The following solubility in mg/l was measured at pH 6.8 for compounds of formula (I) as exemplified below:

solubility 4 15 3 466 10 2 8 49 22 3 Example 150.2 189 37.1 58.5 1.8 79 199 107 234.2 146.5 solubility 3 84 2 43 10 7 11 92 10 4 Example 211.2 183 1.3 212.2 169.3 29.2 52 244 103.2 51.2 solubility >486 10 >458 5 217 14 5 3 129 >429 Example 56.2 180.2 158.2 1.5 213.1 237 142.3 29.1 245 169.2 solubility 4 5 2 3 4 414 136 >403 410 2 Example 2.2 122 154.1 118.1 240 217 88.2 106 87.1 28.3 solubility 41 242 2 13 2 >429 11 35 42 4 Example 73 26 3.6 234.3 40 158.1 180.1 75 10.2 104 solubility >473 128 70 4 9 17 17 21 5 36 Example 195.2 115 118.4 167 30.2 132 185.1 215.3 250 140.1 solubility 16 14 3 14 3 400 150 >417 9 36 Example 202 218 28.2 56.4 35 164 193 142.1 28.1 6.4 solubility 8 30 33 >431 41 2 37 439 >459 240 Example 74 118.2 49 141.1 37.3 27.1 72 195.1 195.3 18 solubility 14 >513 3 65 75 4 47 24 >502 164 Example 41 87.5 53.1 123 146.4 3.5 121 168.2 90.2 54.1 solubility 3 2 18 7 >485 3 >428 8 16 5 Example 64 140.2 8.1 2.3 242.2 148.4 215.2 46 249 190 solubility 6 76 164 102 5 >435 6 5 8 16 Example 1.7 60.2 135 16.2 15.3 54.2 153.1 242.1 61 224.2 solubility 43 3 6 37 2 3 16 2 2 133 Example 243 88.1 146.2 37.4 220.1 69 56.5 32.1 11 81.2 solubility 125 7 15 361 433 9 7 355 >472 59 Example 239 253 3.1 197.1 161 9 5.2 37.2 155.3 176 solubility 33 7 427 445 40 >444 47 13 >486 13 Example 166.1 4.2 137 210 53.2 59.1 70 149.1 175.3 91 solubility 5 10 2 >428 2 12 413 38 58 >456 Example 150.1 15.1 209 16.3 141.2 251 231 103.1 234.1 162 solubility 4 26 4 25 2 9 27 8 16 39 Example 17.3 138 8.2 56.1 29.3 7.2 58.4 186 23.1 12 solubility >487 32 219 >457 62 19 3 >500 8 >484 Example 85.2 17.2 84.1 215.1 155.4 43.1 4.7 3.12 184 139 solubility 72 44 18 >472 >444 55 81 >473 45 >385 Example 133 144.3 207 157 159 212.1 17.1 3.11 23.2 45.1 solubility >544 >434 21 >399 71 14 >443 11 141 14 Example 93.2 146.1 149.2 230 4.3 168.3 215.4 233 136 51.5 solubility 41 300 26 194 5 6 >512 4 5 50 Example 6.2 56.3 3.10 32.2 224.1 85.1 205 30.1 252 2.4 solubility 44 >443 >486 5 >384 8 76 6 >472 8 Example 188 105 63 141.3 10.1 206.1 85.3 125.1 206.2 2.1 solubility 3 32 75 104 30 2 3 225 >428 10 Example 3.7 108 98.2 3.3 113 110 158.3 197.2 58.1 98.3 solubility 10 3 56 16 27 12 74 2 8 24 Example 45.2 89 247.2 220.3 192 203 130 99 173 163 solubility 31 28 >442 53 12 133 4 8 237 7 Example 65 179 165 14 100 208 93.1 98.1 160.2 4.5 solubility 2 >455 65 >442 >458 65 3 4 13 21 Example 66 126 1.6 87.3 155.2 3.9 5.1 27.2 2.5 129 solubility 13 73 >415 289 11 222 6 3 4 25 Example 38 155.1 21.1 169.1 172 87.2 4.6 116 1.4 24 solubility >414 15 21 >459 386 35 336 6 25 246 Example 16.4 16.5 221.1 196.2 127 175.1 4.1 58.3 178 84.2 solubility 4 8 2 3 5 7 6 3 13 3 Example 45.3 44 48 187 51.1 92 59.2 2.7 76 109 solubility 2 2 >481 71 243 83 92 4 56 >441 Example 3.4 67 144.1 15.2 191.2 232 148.1 148.2 182 228 solubility 2 4 >473 69 3 7 2 61 75 94 Example 125.2 152.2 191.1 247.1 117 102 236 114 16.1 194.2 solubility 21 5 11 2 3 >486 169 44 129 32 Example 118.3 171 51.4 2.8 211.1 87.4 177.1 196.1 194.1 160.1 solubility 3 75 315 >469 4 479 8 >458 Example 55 246 1.9 96 131 177.2 238 156

The following permeability log Pe was measured for compound of formula (I) as exemplified below:

Log Pe −3.6 −3.8 −3.8 −3.9 −3.6 −3.4 −3.9 −4.9 −4.4 −4 Example 146.5 27.1 51.1 28.1 37.1 92 3.8 196.1 160.1 248.1 Log Pe −4.4 −4.3 −3.9 −4.7 −4.6 −3.6 −3.9 −3.7 −3.8 −3.7 Example 248.5 189 206.2 150.2 7.2 2.3 28.2 4.6 27.2 84.1 Log Pe −4 −3.9 −3.9 −4.8 −4.5 −4.7 −3.9 −5 −4.4 −3.5 Example 51.3 9 141.3 148.1 141.2 182 250 200 53.1 42 Log Pe −4.6 −4.7 −4.7 −4.7 −4.5 −3.9 −3.8 −4.8 −4.9 −3.9 Example 248.3 24 87.4 135 30.1 2.5 8.1 190 179 173 Log Pe −3.7 −3.9 −3.7 −4 −4.9 −4 −4.7 −4.7 −4.9 −4.5 Example 201 60.1 186 4.4 32.2 5.2 191.1 89 10.1 203 Log Pe −3.8 −3.8 −3.6 −4.4 −5 −3.8 −3.9 −4.5 −3.9 −3.8 Example 113 1.3 90.2 164 103.2 130 146.2 156 4.9 25.4 Log Pe −3.7 −3.6 −3.9 −4.1 −4.7 −3.8 −4.5 −3.9 −3.7 −4.7 Example 2.6 3.11 153.2 209 220.1 234.4 31 85.1 3.5 87.3 Log Pe −3.9 −3.9 −3.5 −3.9 −4 −3.9 −4.2 −4.1 −4.2 −4.1 Example 98.3 98.1 3.4 144.1 19 144.2 53.2 252 161 44 Log Pe −4.4 −4.7 −4 −4.4 −4.5 −4.8 −3.8 −5 −4.2 −3.8 Example 220.3 142.3 61 86 148.3 87.1 128.2 148.2 248.2 98.2 Log Pe −3.7 −4.9 −3.8 −3.8 −4.6 −4.1 −4.2 −3.3 −4 −3.6 Example 13 127 4.1 90.1 25.3 66 132 1.4 4.5 93.1 Log Pe −3.7 −3.7 −4 −3.9 −4.2 −4.5 −4.6 −4.8 −3.8 −3.9 Example 1.2 3.3 146.4 165 221.2 220.2 86.2 136 55 29.1 Log Pe −5.6 −4 −5 −3.7 −3.8 −3.9 −4 −3.9 −4.7 −4.6 Example 93.2 140.2 115 1.7 2.7 3.1 6.3 167 17.3 195.2 Log Pe −4 −3.8 −4.4 −4.1 −3.7 −3.7 −3.7 −3.8 −4.8 −4.1 Example 206.1 145.2 248.4 197.2 8.2 146.3 58.4 1.5 54.2 38 Log Pe −3.6 −4.6 −3.8 −3.8 −4 −3.8 −5 −4.3 −4.3 −4.2 Example 79 233 58.1 82 28.3 56.3 137 240 6.2 150.1 Log Pe −3.8 −4.6 −4.7 −3.9 −4.9 −4.1 −3.8 −4.4 −3.8 −4.9 Example 58.2 104 178 148.4 180.2 1.8 25.5 56.1 35 194.1 Log Pe −4.6 −4.6 −3.8 −4.4 −3.8 −3.8 −3.8 −4.8 −4.2 −3.9 Example 5.1 236 2.8 116 2.4 234.3 6.4 52 184 4.3 Log Pe −4.9 −3.7 −3.7 −4.3 −3.7 −3.7 −4.8 −4.4 −4.2 −4.6 Example 177.2 187 153.1 119 144.3 131 172 30.2 234.1 239 Log Pe −4.3 −4.6 −4.3 −4.2 −4.8 −4 −3.4 −4.5 −4.1 −5.5 Example 183 242.1 249 157 12 29.2 154.2 34 162 211.2 Log Pe −3.9 −4 −4.3 −4.2 −3.7 −5 −3.8 −3.5 −3.6 −3.6 Example 128.1 1.6 213.1 20 37.2 65 50 202 4.8 51.5 Log Pe −5 −3.7 −4.5 −4.4 −3.7 −4.1 −4 −4.1 −5.2 −4.8 Example 197.1 58.3 114 118.1 4.2 191.2 105 154.1 177.1 37.4 Log Pe −4 −3.9 −4.5 −4 −4.4 −3.9 −3.4 −3.4 −4 −3.9 Example 94 85.2 18 11 176 251 3.6 83 1.9 4.7 Log Pe −4.1 −3.8 −4.6 −4.6 −4 −3.8 −4.8 −4.7 −3.7 −3.8 Example 3.2 3.7 160.2 25.1 29.3 56.5 118.5 87.2 91 97 Log Pe −4.1 −4.5 −3.8 −4.8 −4.5 −3.6 −4.6 −4.3 −4 −3.3 Example 146.1 221.1 2.1 59.2 141.1 174 234.2 242.2 56.4 6.1 Log Pe −3.8 −3.8 Example 84.2 84.2

The permeability in 10⁻⁶ cm/s of compounds of formula (I) have been confirmed for selected example using a cellular CaCo2 permeability assay from apical to basal (A-B):

Pe A-B 6.0 20.5 29.4 35.1 39.7 29.9 33.5 29.7 7.7 15.8 Example 96 104 252 4.1 56.1 87.2 54.2 6.4 102 197.1 Pe A-B 17.0 26.7 5.6 35.5 21.0 26.4 24.0 15.9 28.6 22.1 Example 136 84.1 16.2 234.1 3.3 84.2 12 118.4 3.1 249 Pe A-B 30.5 21.5 31.6 7.8 29.1 26.1 18.4 31.2 17.0 10.9 Example 58.1 2.7 1.6 175.1 146.1 189 28.1 3.5 87.1 155.2 Pe A-B 27.8 5.9 16.1 28.6 38.4 26.6 13.9 14.8 16.0 Example 3.7 215.1 4.5 1.8 2.5 6.2 159 3.9 179

Skin Penetration

The skin penetration/permeation properties of two representative compounds of the present invention were tested as follows:

In Vitro Test to Determine Skin Penetration and Permeation Properties

The compounds were applied as 0.5% solutions in propylene glycol to pig skin mounted in static Franz-type diffusion cells. At the end of a 48 hours exposure time, drug concentrations were measured in the skin (after removal of stratum corneum) and in the receiver.

Skin penetration and permeation in vitro Concen- Skin Permeation Formu- tration concentration rate Example Skin lation [%] [μg/g] [ng/cm²/hr] 84.1 Pig+ PG 0.5 6.4 ± 3.5 <0.4 58.1 Pig+ PG 0.5 9.3 ± 6.2 0.5 ± 0.3 Mean ± standard deviation of triplicate determinations are given; +skin from 4 months old farm pigs (Landrace × Deutsches Edelschwein). PG: propylene glycol

In conclusion, both examples penetrate well into pig skin (pig skin is similar to human skin regarding barrier function and architecture) in vitro, while permeation rate through pig skin is low, indicating a low systemic exposure.

In Vivo Test to Determine Penetration into Dermis of Topically Treated Pigs

Small skin areas (4 cm²) on the dorsolateral back of young domestic pigs were treated topically with 0.5% solutions at different time intervals (1-8 hrs) prior to drug level determination. Skin flaps with the treated sites in the centre were dissected and removed. The skin flaps were spread, and heated metal blocks placed on the test sites for 1 minute to induce separation of epidermis from the dermis. After removal of the loosened epidermal sheets, 1 mm thick dermal sheets were prepared from the treated, de-epidermized skin with a dermatome. From these sheets 6 mm punch samples (6 mm Ø) were collected and analysed for test compound concentration by LC/MS. The procedure described was done with careful avoidance of contamination of the dermal samples with compound attached superficially to the epidermis.

The following table provides AUC values of the agents of the invention in pig dermis when applied epicutaneously in the identified compositions (n=8).

Skin PK in vivo Concentration AUC (0-8 h) Example Dermis Formulation [%] [μg*h/g] 84.1 Pig PG/EtOH 7:3 0.5 2.8 ± 1.0 58.1 Pig PG/EtOH 7:3 0.5 3.7 ± 1.3 Mean ± standard error mean of eight determinations are given. PG: propylene glycol EtOH: ethanol

AUC means area under the curve, and is a well known term in clinical pharmacology. The AUC value describes the total uptake of the agent in a time interval.

In conclusion, both examples penetrate well into pig skin in vivo after a single application, confirming in vitro data described above.

Biological Activity

The efficacy of the compounds of formula I and salts thereof as PI3 kinase inhibitors can be demonstrated as follows:

The kinase reaction is performed in a final volume of 50 μL per well of a half area COSTAR, 96 well plate. The final concentrations of ATP and phosphatidyl inositol in the assay are 5 μM and 6 μg/mL respectively. The reaction is started by the addition of PI3 kinase, e.g. PI3 kinase.

p110β.

The components of the assay are added per well as follows:

-   -   10 μL test compound in 5% DMSO per well in columns 2-1.     -   Total activity is determined by addition 10 μL of 5% vol/vol         DMSO in the first 4 wells of column 1 and the last 4 wells of         column 12.     -   The background is determined by addition of 10 μM control         compound to the last 4 wells of column 1 and the first 4 wells         of column 12.     -   2 mL ‘Assay mix’ are prepared per plate:         -   1.912 mL of HEPES assay buffer         -   8.33 μL of 3 mM stock of ATP giving a final concentration of             5 μM per well         -   1 μL of [³³P]ATP on the activity date giving 0.05 μCi per             well         -   30 μL of 1 mg/mL PI stock giving a final concentration of 6             μg/mL per well         -   5 μL of 1 M stock MgCl₂ giving a final concentration of 1 mM             per well     -   20 μL of the assay mix are added per well.     -   2 mL ‘Enzyme mix’ are prepared per plate (×* μL PI3 kinase p110         in 2 mL of kinase buffer). The ‘Enzyme mix’ is kept on ice         during addition to the assay plates. *The volume of enzyme is         dependent on the enzymatic activity of the batch in use.     -   20 μl ‘Enzyme mix’ are added/well to start the reaction.     -   The plate is then incubated at room temperature for 90 minutes.     -   The reaction is terminated by the addition of 50 L WGA-SPA bead         (wheat germ agglutinin-coated Scintillation Proximity Assay         beads) suspension per well.     -   The assay plate is sealed using TopSeal-S) heat seal for         polystyrene microplates, PerkinElmer LAS (Deutschland) GmbH,         Rodgau, Germany) and incubated at room temperature for at least         60 minutes.     -   The assay plate is then centrifuged at 1500 rpm for 2 minutes         using the Jouan bench top centrifuge (Jouan Inc., Nantes,         France).     -   The assay plate is counted using a Packard TopCount, each well         being counted for 20 seconds.

In a more preferred assay, the kinase reaction is performed in a final volume of 10 μL per well of a low volume non binding CORNING, 384 well black plate (Cat. No. #3676). The final concentrations of ATP and phosphatidyl inositol (PI) in the assay are 1 μM and 10 μg/mL respectively. The reaction is started by the addition of ATP.

The components of the assay are added per well as follows:

50 mL test compounds in 90% DMSO per well, in columns 1-20, 8 concentrations (1/3 and 1/3.33 serial dilution step) in single.

-   -   Low control: 50 mL of 90% DMSO in half the wells of columns         23-24 (0.45% in final).     -   High control: 50 mL of reference compound (e.g. compound of         Example 7 in WO 2006/122806) in the other half of columns 23-24         (2.5 μM in final).     -   Standard: 50 mL of reference compound as just mentioned diluted         as the test compounds in columns 21-22     -   20 mL ‘buffer’ are prepared per assay:         -   200 μL of 1M TRIS HCl pH7.5 (10 mM in final)         -   60 μL of 1M MgCl₂ (3 mM in final)         -   500 μL of 2M NaCl (50 mM in final)         -   100 μL of 10% CHAPS (0.05% in final)         -   200 μL of 100 mM DTT (1 mM in final)         -   18.94 mL of nanopure water     -   10 mL ‘PI’ are prepared per assay:         -   200 μL of 1 mg/ml L-alpha-Phosphatidylinositol (Liver             Bovine, Avanti Polar Lipids Cat. No. 840042C MW=909.12)             prepared in 3% OctylGlucoside (10 μg/ml in final)         -   9.8 mL of ‘buffer’     -   10 mL ‘ATP’ are prepared per assay:         -   6.7 μL of 3 mM stock of ATP giving a final concentration of             1 μM per well         -   10 mL of ‘buffer’     -   2.5 mL of each PI3K construct are prepared per assay in ‘PI’         with the following final concentration:         -   10 nM PI3K alfa EMV B1075         -   25 nM beta EMV BV949         -   10 nM delta EMV BV1060         -   150 nM gamma EMV BV950     -   5 μL of ‘PI/PI3K’ are added per well.     -   5 μl ‘ATP’ are added per well to start the reaction.     -   The plates are then incubated at room temperature for 60 minutes         (alfa, beta, delta) or 120 minutes (gamma).     -   The reaction is terminated by the addition of 10 μL Kinase-Glo         (Promega Cat. No. #6714).     -   The assay plates are read after 10 minutes in Synergy 2 reader         (BioTek, Vermont USA) with an integration time of 100         milliseconds and sensitivity set to 191.     -   Output: The High control is around 60'000 counts and the Low         control is 30'000 or lower     -   This luminescence assay gives a useful Z′ ratio between 0.4 and         0.7

The Z′ value is a universal measurement of the robustness of an assay. A Z′ between 0.5 and 1.0 is considered an excellent assay.

For this assay, the PI3K constructs mentioned are prepared as follows:

Molecular Biology:

Two different constructs, BV 1052 and BV 1075, are used to generate the PI3 Kinase a proteins for compound screening.

PI3Kα BV-1052 p85(iSH2)-Gly Linker-p110a(D20aa)-C-Term his Tag

PCR products for the inter SH2 domain (iSH2) of the p85 subunit and for the p110-a subunit (with a deletion of the first 20 amino acids) are generated and fused by overlapping PCR.

The iSH2 PCR product is generated from first strand cDNA using initially primers

gwG130-p01 (5′-CGAGAATATGATAGATTATATGAAGAAT-3′) (SEQ ID NO: 1) and gwG130-p02 (5′-TGGTTT-AATGCTGTTCATACGTTTGTCAAT-3′) (SEQ ID NO: 2). Subsequently in a secondary PCR reaction, Gateway (Invitrogen AG, Basel, Switzerland) recombination AttB1 sites and linker sequences are added at the 5′ end and 3′ end of the p85 iSH2 fragment respectively, using primers

gwG130-p03 (5′-GGGACAAGTTTGTACAAAAAAGCAGGCTACGAAGGAGATATACATAT-GCGAGAATATGATAGATTATATGAAGAAT-3′) (SEQ ID NO: 3) and

gwG152-p04 (5′-TACCATAATTCCACCACCACCACCGGAAATTCCCCCTGGTTT-AATGCTGTTCATACGTTTGTCAAT-3′) (SEQ ID NO: 4).

The p110-a fragment is also generated from first strand cDNA, initially using primers gwG152-p01 (5′-CTAGTGGAATGTTTACTACCAAATGG-3) (SEQ ID NO: 5) and

gwG152-p02 (5′-GTTCAATG-CATGCTGTTTAATTGTGT-3′) (SEQ ID NO: 6).

In a subsequent PCR reaction, linker sequence and a Histidine tag are added at the 5′ end and 3′ end of the p110-a fragment respectively, using primers

gw152-p03 (5′-GGGGGAATTTCCGGTGGTGGTGGTGGAATTATGGTAC-TAGTGGAATGTTTACTACC-AAATGGA-3′) (SEQ ID NO: 7) and

gwG152-p06 (5′-AGCTCCGTGATGGTGATGGTGATGTGCTCCGTTCAATG-CATGCTGTTTAATTGTGT-3′) (SEQ ID NO: 8).

The p85-iSH2/p110-a fusion protein is assembled in a third PCR reaction by the overlapping linkers at the 3′ end of the iSH2 fragment and the 5′ end of the p110-a fragment, using the above mentioned gwG130-p03 primer and a primer containing an overlapping Histidine tag and the AttB2 recombination sequences

(5′-GGGACCACTTTGTACAAGAAAGCTGGGTTTAAGCTCCGTGATGGTGATGGTGAT-GTGCTCC-3′) (SEQ ID NO: 9).

This final product is recombined in a (Invitrogen) OR reaction into the donor vector pDONR201 to generate the ORF318 entry clone. This clone is verified by sequencing and used in a Gateway LR reaction to transfer the insert into the Gateway adapted pBlueBac4.5 (Invitrogen) vector for generation of the baculovirus expression vector LR410.

PI3Kα BV-1075 p85(iSH2)-12 XGly Linker-p110a(D20aa)-C-Term his Tag

The construct for Baculovirus BV-1075 is generated by a three-part ligation comprised of a p85 fragment and a p110-a fragment cloned into vector pBlueBac4.5. The p85 fragment is derived from plasmid p1661-2 digested with Nhe/Spe. The p110-a fragment derived from LR410 (see above) as a SpeI/HindIII fragment. The cloning vector pBlueBac4.5 (Invitrogen) is digested with Nhe/HindIII. This results in the construct PED 153.8

The p85 component (iSH2) is generated by PCR using ORF 318 (described above) as a template and one forward primer

KAC1028 (5′-GCTAGCATGCGAGAATATGATAGATTATATGAAGAATATACC) (SEQ ID NO: 10) and two reverse primers,

KAC1029 (5′-GCCTCCACCACCTCCGCCTGGTTTAATGCTGTTCATACGTTTGTC) (SEQ ID NO: 11) and

KAC1039 (5′-TACTAGTCCGCCTCCACCACCTCCGCCTCCACCACCTCCGCC) (SEQ ID NO: 12).

The two reverse primers overlap and incorporate the 12× Gly linker and the N-terminal sequence of the p110a gene to the SpeI site. The 12× Gly linker replaces the linker in the BV1052 construct. The PCR fragment is cloned into pCR2.1 TOPO (Invitrogen). Of the resulting clones, p1661-2 is determined to be correct. This plasmid is digested with Nhe and SpeI and the resulting fragment is gel-isolated and purified for sub-cloning.

The p110-a cloning fragment is generated by enzymatic digest of clone LR410 (see above) with Spe I and HindIII. The SpeI site is in the coding region of the p110a gene. The resulting fragment is gel-isolated and purified for sub-cloning.

The cloning vector, pBlueBac4.5 (Invitrogen) is prepared by enzymatic digestion with Nhe and HindIII. The cut vector is purified with Qiagen (Quiagen N.V, Venlo, Netherlands) column and then dephosphorylated with Calf Intestine alkaline phosphatase (CIP) (New England BioLabs, Ipswich, Mass.). After completion of the CIP reaction the cut vector is again column purified to generate the final vector. A 3 part ligation is performed using Roche Rapid ligase and the vendor specifications.

PI3Kβ BV-949 p85(iSH2)-Gly Linker-p110b(Full-Length)-C-Term his Tag

PCR products for the inter SH2 domain (iSH2) of the p85 subunit and for the full-length p110-b subunit are generated and fused by overlapping PCR.

The iSH2 PCR product is generated from first strand cDNA initially using primers gwG130-p01 (5′-CGAGAATATGATAGATTATATGAAGAAT-3′) (SEQ ID NO: 1) and gwG130-p02 (5′-TGGTTT-AATGCTGTTCATACGTTTGTCAAT-3′) (SEQ ID NO: 2). Subsequently, in a secondary PCR reaction Gateway (Invitrogen) recombination AttB1 sites and linker sequences are added at the 5′ end and 3′ end of the p85 iSH2 fragment respectively, using primers

gwG130-p03 (5′-GGGACAAGTTTGTACAAAAAAGCAGGCTACGAAGGAGATA-TACATATGCGAGAATATGATAGATTATATGAAGAAT-3) (SEQ ID NO: 3) and

gwG130-p05 (5′-ACTGAAGCATCCTCCTCCTCCTCCTCCTGGTTTAAT-GCTGTTCATACGTTTGTC-3) (SEQ ID NO: 13).

The p110-b fragment is also generated from first strand cDNA initially using primers gwG130-p04 (5′-ATTAAACCAGGAGGAGGAGGAGGAGGATGCTTCAGTTTCATAATGCC-TCCTGCT-3′) (SEQ ID NO: 4)

which contains linker sequences and the 5′ end of p110-b and

gwG130-p06 (5′-AGCTCCGTGATGGTGATGGTGATGTGCTCCAGATCTGTAGTCTTT-CCGAACTGTGTG-3) (SEQ ID NO: 14)

which contains sequences of the 3′ end of p110-b fused to a Histidine tag.

The p85-iSH2/p110-b fusion protein is assembled by an overlapping PCR a reaction of the linkers at the 3′ end of the iSH2 fragment and the 5′ end of the p110-b fragment, using the above mentioned gwG130-p03 primer and a primer containing an overlapping Histidine tag and the AttB2 recombination sequences (5′-GGGACCACTTTGTACAAGAAAGCTGGGTTT-AAGCTCCGTGATGGTGATGGTGATGTGCTCC-3′) (SEQ ID NO: 9).

This final product is recombined in a Gateway (Invitrogen) OR reaction into the donor vector pDONR201 to generate the ORF253 entry clone. This clone is verified by sequencing and used in a Gateway LR reaction to transfer the insert into the Gateway adapted pBlueBac4.5 (Invitrogen) vector for generation of the baculovirus expression vector LR280.

PI3Kγ BV-1060 p85(iSH2)-Gly Linker-p110d(Full-Length)-C-Term his Tag

PCR products for the inter SH2 domain (iSH2) of the p85 subunit and for the full-length p110-d subunit are generated and fused by overlapping PCR.

The iSH2 PCR product is generated from first strand cDNA using initially primers

gwG130-p01 (5′-CGAGAATATGATAGATTATATGAAGAAT-3′) (SEQ ID NO: 1) and gwG130-p02 (5′-TGGTTT-AATGCTGTTCATACGTTTGTCAAT-3′) (SEQ ID NO: 2). Subsequently, in a secondary PCR reaction Gateway (Invitrogen) recombination AttB1 sites and linker sequences are added at the 5′ end and 3′ end of the p85 iSH2 fragment respectively, using primers

gwG130-p03 (5′-GGGACAAGTTTGTACAAAAAAGCAGGCTACGAAGGAGATATACAT-ATGCGAGAATATGATAGATTATATGAAGAAT-3) (SEQ ID NO: 3) and

gwG154-p04 (5′-TCCTCCTCCTCCTCCTCCTGGTTTAATGCTGTTCATACGTTTGTC-3′) (SEQ ID NO: 15).

The p110-a fragment is also generated from first strand cDNA using initially primers gwG154-p01 (5′-ATGCCCCCTGGGGTGGACTGCCCCAT-3′) (SEQ ID NO: 16) and gwG154-p02 (5′-CTACTG-CCTGTTGTCTTTGGACACGT-3) (SEQ ID NO: 17).

In a subsequent PCR reaction linker sequences and a Histidine tag is added at the 5′ end and 3′ end of the p110-d fragment respectively, using primers

gw154-p03 (5′-ATTAAACCAGGAGGAGGAGGAGGAGGACCCCCTGGGGTGGAC-TGCCCCATGGA-3) (SEQ ID NO: 18) and gwG154-p06 (5′-AGCTCCGTGATGGTGAT-GGTGATGTGCT-CCCTGCCTGTTGTCTTTGGACACGTTGT-3′) (SEQ ID NO: 19).

The p85-iSH2/p110-d fusion protein is assembled in a third PCR reaction by the overlapping linkers at the 3′ end of the iSH2 fragment and the 5′ end of the p110-d fragment, using the above mentioned gwG130-p03 primer and a primer containing an overlapping Histidine tag and the Gateway (Invitrogen) AttB2 recombination sequences (5′-GGGACCACTTTGTA-CAAGAAAGCTGGGTTT-AAGCTCCGTGATGGTGATGGTGATGTGCTCC-3) (SEQ ID NO: 09).

This final product is recombined in a Gateway (Invitrogen) OR reaction into the donor vector pDONR201 to generate the ORF319 entry clone. This clone is verified by sequencing and used in a Gateway LR reaction to transfer the insert into the Gateway adapted pBlueBac4.5 (Invitrogen) vector for generation of the baculovirus expression vector LR415.

PI3Kγ BV-950 p110g(D144aa)-C-Term his Tag

This construct is obtained from Roger Williams lab, MRC Laboratory of Molecular Biology, Cambridge, UK (November, 2003). Description of the construct in: Pacold M. E. et al. (2000) Cell 103, 931-943.

Expression:

Methods to generate recombinant baculovirus and protein for PI3K isoforms:

The pBlue-Bac4.5 (for a, b, and d isoforms) or pVL1393 (for g) plasmids containing the different PI3 kinase genes are co-transfected with BaculoGold WT genomic DNA (BD Biosciences, Franklin Lakes, N.J., USA) using methods recommended by the vendor. Subsequently, the recombinant baculovirus obtained from the transfection is plaque-purified on Sf9 insect cells to yield several isolates expressing recombinant protein. Positive clones are selected by anti-HIS or anti-isoform antibody western. For PI3K alpha and delta isoforms, a secondary plaque-purification is performed on the first clonal virus stocks of PI3K. Amplification of all baculovirus isolates is performed at low multiplicity of infection (moi) to generate high-titer, low passage stock for protein production. The baculoviruses are designated BV1052 (α) and BV1075 (α), BV949 (β), BV1060 (δ) and BV950 (γ).

Protein production involves infection (passage 3 or lower) of suspended Tn5 (Trichoplusia ni) or TiniPro (Expression Systems, LLC, Woodland, Calif., USA) cells in protein-free media at moi of 2-10 for 39-48 hours in 2 L glass Erlenmyer flasks (110 rpm) or wave-bioreactors (22-25 rpm). Initially, 10 L working volume wave-bioreactors are seeded at a density of 3e5 cells/ml at half capacity (5 L). The reactor is rocked at 15 rpm during the cell growth phase for 72 hours, supplemented with 5% oxygen mixed with air (0.2 L per minute). Immediately prior to infection, the wave-reactor cultures are analyzed for density, viability and diluted to approximately 1.5e6 cell/ml. 100-500 ml of high titer, low passage virus is added following 2-4 hours of additional culture. Oxygen is increased to 35% for the 39-48 hour infection period and rocking platform rpm increased to 25. During infection, cells are monitored by Vicell viability analyzer (Beckman Coulter, Inc, Fullerton, Calif., USA) bioprocess for viability, diameter and density. Nova Bioanalyzer (NOVA Biomedical Corp., Waltham, Mass., USA) readings of various parameters and metabolites (pH, O₂ saturation, glucose, etc.) are taken every 12-18 hours until harvest. The wave-bioreactor cells are collected within 40 hours post infection. Cells are collected by centrifugation (4 degrees C. at 1500 rpm), and subsequently maintained on ice during pooling of pellets for lysis and purification. Pellet pools are made with small amounts of cold, un-supplemented Grace's media (w/o protease inhibitors).

PI3K Alpha Purification Protocol for HTS (BV1052)

PI3K alpha is purified in three chromatographic steps: immobilized metal affinity chromatography on a Ni Sepharose resin (GE Healthcare, belonging to General Electric Company, Fairfield, Conn., USA), gel filtration utilizing a Superdex 200 26/60 column (GE Healthcare), and finally a cation exchange step on a SP-XL column (GE Healthcare). All buffers are chilled to 4° C. and lysis is performed chilled on ice. Column fractionation is performed rapidly at room temperature.

Typically frozen insect cells are lysed in a hypertonic lysis buffer and applied to a prepared IMAC column. The resin is washed with 3-5 column volumes of lysis buffer, followed by 3-5 column volumes wash buffer containing 45 mM imidazole, and the target protein is then eluted with a buffer containing 250 mM imidazole. Fractions are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing target protein are pooled and applied to a prepared GFC column. Fractions from the GFC column are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing target protein are pooled. The pool from the GFC column is diluted into a low salt buffer and applied to a prepared SP-XL column. The column is washed with low salt buffer until a stable A280 baseline absorbance is achieved, and eluted using a 20 column volume gradient from 0 mM NaCl to 500 mM NaCl. Again, fractions from the SP-XL column are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing the target protein are pooled. The final pool is dialyzed into a storage buffer containing 50% glycerol and stored at −20° C. The final pool is assayed for activity in a phosphoinosititol kinase assay.

PI3K Beta Purification Protocol for HTS (BV949)

PI3K beta is purified in two chromatographic steps: immobilized metal affinity chromatography (IMAC) on a Ni Sepharose resin (GE Healthcare) and gel filtration (GFC) utilizing a Superdex 200 26/60 column (GE Healthcare). All buffers are chilled to 4° C. and lysis is performed chilled on ice. Column fractionation is performed rapidly at room temperature.

Typically frozen insect cells are lysed in a hypertonic lysis buffer and applied to a prepared IMAC column. The resin is washed with 3-5 column volumes of lysis buffer, followed by 3-5 column volumes wash buffer containing 45 mM imidazole, and the target protein is then eluted with a buffer containing 250 mM imidazole. Fractions are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing target protein are pooled and applied to a prepared GFC column. Fractions from the GFC column are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing target protein are pooled. The final pool is dialyzed into a storage buffer containing 50% glycerol and stored at −20° C. The final pool is assayed for activity in the phosphoinostitol kinase assay.

PI3K Gamma Purification Protocol for HTS (BV950)

PI3K gamma is purified in two chromatographic steps: immobilized metal affinity chromatography (IMAC) on a Ni Sepharose resin (GE Healthcare) and gel filtration (GFC) utilizing a Superdex 200 26/60 column (GE Healthcare). All buffers are chilled to 4° C. and lysis is performed chilled on ice. Column fractionation is performed rapidly at room temperature. Typically frozen insect cells are lysed in a hypertonic lysis buffer and applied to a prepared IMAC column. The resin is washed with 3-5 column volumes of lysis buffer, followed by 3-5 column volumes wash buffer containing 45 mM imidazole, and the target protein is then eluted with a buffer containing 250 mM imidazole. Fractions are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing target protein are pooled and applied to a prepared GFC column. Fractions from the GFC column are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing target protein are pooled. The final pool is dialyzed into a storage buffer containing 50% glycerol and stored at −20° C. The final pool is assayed for activity in the phosphoinostitol kinase assay.

PI3K Delta Purification Protocol for HTS (BV1060)

PI3K delta is purified in three chromatographic steps: immobilized metal affinity chromatography on a Ni Sepharose resin (GE Healthcare), gel filtration utilizing a Superdex 200 26/60 column (GE Healthcare), and finally a anion exchange step on a Q-HP column (GE Healthcare). All buffers are chilled to 4° C. and lysis is performed chilled on ice. Column fractionation is performed rapidly at room temperature. Typically frozen insect cells are lysed in a hypertonic lysis buffer and applied to a prepared IMAC column. The resin is washed with 3-5 column volumes of lysis buffer, followed by 3-5 column volumes wash buffer containing 45 mM imidazole, and the target protein is then eluted with a buffer containing 250 mM imidazole. Fractions are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing the target protein are pooled and applied to a prepared GFC column. Fractions from the GFC column are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing the target protein are pooled. The pool from the GFC column is diluted into a low salt buffer and applied to a prepared Q-HP column. The column is washed with low salt buffer until a stable A280 baseline absorbance is achieved, and eluted using a 20 column volume gradient from 0 mM NaCl to 500 mM NaCl. Again, fractions from the Q-HP column are analyzed by Coomassie stained SDS-PAGE gels, and fractions containing the target protein are pooled. The final pool is dialyzed into a storage buffer containing 50% glycerol and stored at −20° C. The final pool is assayed for activity in the phosphoinostitol kinase assay.

IC50 is determined by a four parameter curve fitting routine that comes along with “excel fit”. A 4 Parameter logistic equation is used to calculate IC₅₀ values (IDBS XLfit) of the percentage inhibition of each compound at 8 concentrations (usually 10, 3.0, 1.0, 0.3, 0.1, 0.030, 0.010 and 0.003 μM). Alternatively, IC50 values are calculated using idbsXLfit model 204, which is a 4 parameter logistic model.

Yet alternatively, for an ATP depletion assay, compounds of the formula (I) to be tested are dissolved in DMSO and directly distributed into a white 384-well plate at 0.5 μL per well. To start the reaction, 10 μL of 10 nM PI3 kinase and 5 μg/mL 1-alpha-phosphatidylinositol (PI) are added into each well followed by 10 μL of 2 μM ATP. The reaction is performed until approx 50% of the ATP is depleted, and then stopped by the addition of 20 μL of Kinase-Glo solution (Promega Corp., Madison, Wis., USA). The stopped reaction is incubated for 5 minutes and the remaining ATP is then detected via luminescence. IC₅₀ values are then determined.

Some of the compounds of formula (I) show a certain level of selectivity against the different paralogs PI3K alpha, beta, gamma and delta.

The range of activity, expressed as IC₅₀, in these assays is preferably between 1 nM and 5000 nM, more preferably between 1 nM and about 1000 nM

PI3K alpha IC₅₀ [nM] 9 60 155 5 37 62 14 18 16 17 Example 182 4.1 56.5 56.4 124 2.2 177.1 148.2 119 107 PI3K alpha IC₅₀ [nM] 138 39 44 11 21 42 5 39 12 938 Example 132 82 175.3 128.2 3.9 103.2 110 179 116 133 PI3K alpha IC₅₀ [nM] 35 11 9 61 25 24 4 30 70 86 Example 146.4 243 36 3.7 56.2 2.7 189 17.1 42 18 PI3K alpha IC₅₀ [nM] 59 92 <3 14 7 10 12 18 83 30 Example 1.7 146.6 234.2 207 34 239 215.1 195.1 91 30.2 PI3K alpha IC₅₀ [nM] 20 63 19 70 9 33 32 13 125 4 Example 234.1 149.3 193 177.2 168.3 167 171 218 155.4 56.1 PI3K alpha IC₅₀ [nM] 8 65 4 23 56 7 10 6 50 13 Example 248.2 2.4 194.2 4.5 55 32.1 166.3 211.2 125.2 191.2 PI3K alpha IC₅₀ [nM] 30 9 <3 8 6 23 12 42 91 44 Example 155.3 87.3 60.1 1.6 58.2 168.2 13 87.4 3.10 152.3 PI3K alpha IC₅₀ [nM] 8 9 27 28 16 215 22 14 9 11 Example 144.2 33 152.1 246 99 212.2 51.4 155.2 17.3 202 PI3K alpha IC₅₀ [nM] 14 14 32 39 4 26 87 210 18 8 Example 45.1 25.1 21.2 172 184 16.2 64 8.1 241 237 PI3K alpha IC₅₀ [nM] 11 94 76 5 17 85 28 14 11 30 Example 254 2.1 135 249 198 97 125.1 141.2 128.1 93.2 PI3K alpha IC₅₀ [nM] 20 18 11 6 56 14 24 79 51 48 Example 127 14 120 76 52 75 210 104 126 4.6 PI3K alpha IC₅₀ [nM] <3 123 59 817 20 27 27 28 9 6 Example 39 15.3 16.3 141.1 248.1 51.3 145.2 1.9 166.4 240 PI3K alpha IC₅₀ [nM] 99 10 17 184 10 61 146 37 70 3 Example 4.3 24 176 16.4 1.5 51.6 3.3 3.5 44 252 PI3K alpha IC₅₀ [nM] 119 7 17 7 27 22 161 29 10 20 Example 146.2 150.1 54.1 148.3 111 180.2 137 31 248.3 74 PI3K alpha IC₅₀ [nM] 17 118 9 14 29 9 16 64 47 22 Example 88.2 98.2 4.9 7.2 72 188 15.1 234.4 96 6.2 PI3K alpha IC₅₀ [nM] 43 41 157 100 38 50 56 36 73 94 Example 87.5 186 154.1 230 29.2 3.6 17.2 95 47 53.2 PI3K alpha IC₅₀ [nM] 17 18 12 7 5 163 8 11 8 41 Example 152.2 89 86 157 203 247.3 23.1 185.2 6.3 25.6 PI3K alpha IC₅₀ [nM] 15 20 461 24 14 482 11 13 7 110 Example 187 103.1 4.7 169.1 160.1 19 29.3 155.1 165 51.5 PI3K alpha IC₅₀ [nM] 14 5 13 29 17 15 3 11 220 34 Example 215.2 77 138 238 174 208 183 118.2 213.2 5.2 PI3K alpha IC₅₀ [nM] 60 7 5 11 14 375 55 8 6 246 Example 6.4 58.5 101 88.1 146.1 70 170 229 211.1 9 PI3K alpha IC₅₀ [nM] 161 7 59 9 9 71 8 6 462 38 Example 131 149.2 25.3 158.1 220.1 37.3 12 209 213.1 57 PI3K alpha IC₅₀ [nM] 8 13 34 22 30 6 26 100 14 15 Example 215.3 221.2 85.3 30.1 244 22 206.1 148.4 87.1 234.3 PI3K alpha IC₅₀ [nM] 15 34 74 15 58 14 10 82 30 250 Example 195.4 98.1 83 166.2 117 158.5 144.3 56.3 87.2 37.2 PI3K alpha IC₅₀ [nM] 39 23 48 199 36 5 44 9 78 26 Example 69 173 27.2 175.2 144.1 205 90.2 1.10 3.2 148.1 PI3K alpha IC50 [nM] 6 29 5 12 110 15 32 51 34 9 Example 1.8 2.8 35 181 105 236 248.5 81.2 37.1 86.2 PI3K alpha IC₅₀ [nM] 15 8 39 43 16 14 46 57 188 25 Example 4.2 51.2 160.2 222 156 122 85.2 3.12 50 136 PI3K alpha IC₅₀ [nM] 13 132 186 9 971 16 5 4 47 4 Example 190 108 206.2 118.5 247.5 10.2 185.1 84.2 49 93.1 PI3K alpha IC₅₀ [nM] 5 22 5 21 9 28 9 28 217 42 Example 169.3 233 220.3 141.3 150.2 166.5 166.1 142.1 3.4 145.1 PI3K alpha IC₅₀ [nM] 175 5 14 154 6 103 10 14 785 44 Example 196.2 250 221.1 106 151 26 43.1 168.1 130 232 PI3K alpha IC₅₀ [nM] 4 10 43 146 6 9 45 29 74 95 Example 201 153.1 90.1 2.6 85.1 200 4.4 196.1 45.2 8.2 PI3K alpha IC₅₀ [nM] 46 93 29 42 8 30 82 24 33 30 Example 7.1 224.2 6.1 80.2 43.2 32.2 178 29.1 226 5.1 PI3K alpha IC₅₀ [nM] 85 28 5 14 61 148 12 22 168 34 Example 228 251 164 58.4 62 115 25.4 245 140.1 159 PI3K alpha IC₅₀ [nM] 41 19 17 25 8 7 18 16 249 66 Example 197.2 143 139 147 27.1 158.3 142.2 3.8 15.2 175.1 PI3K alpha IC₅₀ [nM] 446 7 34 34 39 8 9 3 460 41 Example 123 248.4 194.1 197.1 1.4 38 161 223 65 180.1 PI3K alpha IC₅₀ [nM] 12 8 12 543 21 18 20 207 173 12 Example 61 217 109 134 3.1 59.1 225 3.11 73 219 PI3K alpha IC₅₀ [nM] 13 8 <3 5 272 36 17 21 81 72 Example 25.2 162 192 59.2 21.1 66 2.5 68 242.2 158.4 PI3K alpha IC₅₀ [nM] 30 12 136 38 44 75 79 16 37 43 Example 25.5 129 10.1 247.2 158.2 81.1 112 53.1 195.2 2.9 PI3K alpha IC₅₀ [nM] 4 48 48 15 92 <9 15 6 6 16 Example 253 195.3 79 199 63 41 224.1 163 58.1 118.3 PI3K alpha IC₅₀ [nM] 104 6 53 173 26 33 93 50 10 35 Example 92 84.1 212.1 154.2 118.1 16.1 247.1 146.3 220.2 23.2 PI3K alpha IC₅₀ [nM] 405 50 266 14 139 55 30 62 315 20 Example 231 46 37.4 1.3 153.3 98.3 2.3 28.2 60.2 118.4 PI3K alpha IC₅₀ [nM] 20 19 13 13 236 71 <3 76 30 14 Example 40 121 28.3 102 58.3 227 28.1 45.3 54.2 191.1 PI3K alpha IC₅₀ [nM] 3 50 15 48 34 23 18 23 25 6 Example 16.5 1.2 153.2 149.1 169.2 242.1 100 51.1 142.3 215.4 PI3K alpha IC₅₀ [nM] 9 Example 146.5 PI3K beta IC₅₀ [nM] 252 10 206 17 7 11 28 13 370 7 Example 18 158.1 116 211.2 220.3 182 54.1 39 74 168.3 PI3K beta IC₅₀ [nM] 241 13 24 161 150 37 506 184 122 48 Example 2.1 239 77 195.3 234.3 166.1 49 158.2 27.1 25.3 PI3K beta IC₅₀ [nM] 274 31 123 19 166 39 504 14 59 537 Example 178 28.3 3.8 25.1 2.9 1.9 251 153.1 4.9 3.7 PI3K beta IC₅₀ [nM] 40 6 134 6 68 10 407 83 302 163 Example 38 192 222 194.2 149.1 163 98.1 62 118.1 195.2 PI3K beta IC₅₀ [nM] 21 185 112 103 44 33 130 19 391 51 Example 158.5 6.2 72 197.2 225 99 179 59.2 112 148.1 PI3K beta IC₅₀ [nM] 83 79 21 167 559 120 16 67 382 213 Example 124 152.1 12 146.5 175.3 2.4 144.3 242.1 4.3 4.5 PI3K beta IC₅₀ [nM] 56 101 129 32 340 114 43 140 404 61 Example 185.2 153.3 1.3 198 3.5 147 32.1 100 7.1 68 PI3K beta IC₅₀ [nM] 332 51 6 344 12 20 68 799 9 843 Example 103.2 6.3 56.4 230 87.3 162 88.2 10.1 185.1 53.2 PI3K beta IC₅₀ [nM] 120 17 7 17 246 526 197 21 38 46 Example 17.1 150.1 237 160.1 92 15.3 23.2 86.2 109 155.3 PI3K beta IC₅₀ [nM] 359 110 17 112 62 152 28 19 239 192 Example 234.4 63 128.2 41 254 1.7 187 218 30.2 3.1 PI3K beta IC₅₀ [nM] 25 35 56 40 44 82 281 34 18 495 Example 13 128.1 43.2 215.1 127 118.2 81.2 129 161 6.4 PI3K beta IC₅₀ [nM] 103 733 33 28 16 12 33 109 28 322 Example 238 4.4 152.2 88.1 25.4 85.1 249 2.8 157 64 PI3K beta IC₅₀ [nM] 336 291 35 335 23 13 385 126 787 23 Example 4.6 102 148.2 87.5 89 200 142.3 93.2 5.1 248.3 PI3K beta IC₅₀ [nM] 432 104 71 25 111 132 41 41 115 9 Example 206.2 203 248.1 234.2 143 28.2 118.5 220.2 90.2 153.2 PI3K beta IC₅₀ [nM] 228 22 157 22 86 68 91 163 165 23 Example 56.3 87.2 30.1 122 10.2 168.2 2.7 105 32.2 221.1 PI3K beta IC₅₀ [nM] 76 8 324 188 7 69 15 15 72 29 Example 154.2 229 194.1 244 169.3 58.5 28.1 34 195.1 45.2 PI3K beta IC₅₀ [nM] 21 23 46 473 377 167 13 193 578 612 Example 151 220.1 33 3.11 138 207 86 56.5 25.2 2.6 PI3K beta IC₅₀ [nM] 39 42 51 278 287 5 409 27 76 56 Example 233 180.1 54.2 2.2 142.2 215.3 91 199 208 66 PI3K beta IC₅₀ [nM] 49 145 207 287 407 81 5 162 119 13 Example 210 171 146.3 227 141.3 166.2 58.2 145.1 234.1 217 PI3K beta IC₅₀ [nM] 19 80 112 91 25 515 17 95 20 25 Example 155.1 144.1 158.4 81.1 165 16.4 205 148.4 119 61 PI3K beta IC₅₀ [nM] 79 36 477 61 517 144 28 93 281 180 Example 152.3 174 3.6 125.1 26 248.5 16.5 87.4 146.6 2.3 PI3K beta IC₅₀ [nM] 57 43 6 34 100 17 50 10 101 169 Example 29.1 1.6 1.10 168.1 159 155.2 193 215.2 232 45.3 PI3K beta IC₅₀ [nM] 24 18 23 178 12 8 144 101 66 98 Example 252 177.1 101 191.2 149.2 158.3 29.3 1.5 146.2 154.1 PI3K beta IC₅₀ [nM] 162 173 171 62 45 29 184 41 6 39 Example 245 27.2 16.2 224.1 146.1 221.2 241 23.1 201 90.1 PI3K beta IC₅₀ [nM] 84 142 280 167 95 133 22 37 130 10 Example 167 141.2 224.2 29.2 107 25.6 248.2 35 118.4 166.4 PI3K beta IC₅₀ [nM] 66 802 3 603 387 29 18 222 93 49 Example 7.2 126 148.3 242.2 8.2 156 211.1 166.5 125.2 219 PI3K beta IC₅₀ [nM] 47 811 206 762 12 273 4 970 343 41 Example 45.1 47 17.2 4.1 215.4 209 93.1 37.1 52 111 PI3K beta IC₅₀ [nM] 468 7 129 87 47 13 6 695 73 77 Example 197.1 58.1 69 169.1 243 181 56.1 118.3 186 196.1 PI3K beta IC₅₀ [nM] 81 176 378 130 988 33 13 327 37 288 Example 166.3 146.4 1.4 160.2 15.2 176 202 177.2 75 80.2 PI3K beta IC₅₀ [nM] 67 201 90 544 38 11 227 89 8 3 Example 31 142.1 236 96 206.1 22 6.1 59.1 84.1 60.1 PI3K beta IC₅₀ [nM] 34 93 24 395 946 26 101 86 10 225 Example 40 121 195.4 170 21.1 24 103.1 2.5 76 4.2 PI3K beta IC₅₀ [nM] 29 51 24 7 190 165 30 218 137 37 Example 58.4 53.1 191.1 223 43.1 169.2 25.5 44 110 17.3 PI3K beta IC₅₀ [nM] 205 907 30 139 404 317 10 477 5 280 Example 21.2 117 188 85.2 16.3 56.2 184 85.3 189 1.2 PI3K beta IC₅₀ [nM] 20 146 32 255 68 130 18 71 228 154 Example 1.8 172 36 15.1 250 14 120 226 16.1 82 PI3K beta IC₅₀ [nM] 951 41 82 161 202 8 148 50 563 12 Example 55 95 246 132 149.3 248.4 173 145.2 46 150.2 PI3K beta IC₅₀ [nM] 21 40 11 8 42 180 215 4 469 30 Example 87.1 144.2 164 253 180.2 175.1 57 183 141.1 84.2 PI3K beta IC₅₀ [nM] 91 36 401 203 55 Example 240 190 3.3 58.3 155.4 PI3K delta IC₅₀ [nM] 44 24 8 234 40 4 14 91 166 28 Example 6.4 36 203 83 125.2 158.3 171 4.6 228 6.1 PI3K delta IC₅₀ [nM] 9 800 101 118 24 <3 9 16 10 16 Example 119 115 98.2 51.1 95 201 157 116 246 62 PI3K delta IC₅₀ [nM] 37 <3 29 441 271 8 5 15 9 11 Example 52 248.3 68 42 131 150.1 253 233 89 168.2 PI3K delta IC₅₀ [nM] 10 922 71 7 11 13 10 56 4 15 Example 120 137 103.2 1.5 1.6 118.2 200 29.2 183 158.1 PI3K delta IC₅₀ [nM] 141 58 129 5 8 5 25 148 50 16 Example 104 132 56.3 86 249 192 159 3.3 27.2 146.1 PI3K delta IC₅₀ [nM] 53 147 87 20 19 75 28 13 283 50 Example 5.2 241 179 17.1 103.1 51.3 107 219 3.4 111 PI3K delta IC₅₀ [nM] 85 4 45 7 292 30 18 57 32 598 Example 2.6 88.1 148.4 220.2 10.1 146.2 1.9 85.2 25.6 51.4 PI3K delta IC₅₀ [nM] 4 24 69 9 7 12 10 38 41 329 Example 25.4 181 139 145.2 158.5 4.9 146.6 32.2 24 15.3 PI3K delta IC₅₀ [nM] 9 8 40 <3 36 465 20 3 17 44 Example 234.1 182 3.5 166.4 30.1 37.2 54.2 85.1 4.5 141.1 PI3K delta IC₅₀ [nM] 10 4 372 9 14 43 19 235 9 89 Example 45.3 142.1 73 22 155.1 3.7 234.4 175.2 144.3 4.4 PI3K delta IC₅₀ [nM] 12 8 30 5 5 126 68 5 24 794 Example 53.1 58.1 81.2 151 229 175.3 7.1 163 197.2 247.2 PI3K delta IC₅₀ [nM] 5 7 56 15 26 160 17 57 386 3 Example 168.1 252 2.2 194.1 225 196.2 193 206.2 130 146.5 PI3K delta IC₅₀ [nM] 120 932 4 33 336 6 121 9 7 3 Example 8.2 133 164 142.2 26 191.1 56.2 59.2 198 220.3 PI3K delta IC₅₀ [nM] 777 15 11 17 6 15 18 118 144 18 Example 247.1 101 190 61 221.2 13 118.1 58.3 5.1 21.2 PI3K delta IC₅₀ [nM] 6 6 3 6 647 112 19 <3 13 19 Example 218 208 153.2 202 212.2 10.2 45.1 194.2 7.2 217 PI3K delta IC₅₀ [nM] <3 127 33 737 7 196 6 11 5 28 Example 60.1 92 2.4 9 206.1 56.5 99 158.4 196.1 44 PI3K delta IC₅₀ [nM] 37 175 16 3 106 13 10 4 3 437 Example 173 65 160.2 153.1 49 25.1 215.4 144.2 239 230 PI3K delta IC₅₀ [nM] 12 102 23 394 33 47 25 11 77 29 Example 177.1 126 40 3.2 172 32.1 80.2 191.2 82 207 PI3K delta IC₅₀ [nM] 236 170 19 19 5 51 31 52 26 48 Example 97 251 66 87.2 195.4 64 90.1 105 125.1 98.1 PI3K delta IC₅₀ [nM] 9 37 98 8 721 98 111 10 147 84 Example 127 3.1 141.2 152.1 3.12 4.3 212.1 143 117 118.3 PI3K delta IC₅₀ [nM] 34 9 163 4 42 12 40 11 5 262 Example 195.3 211.2 70 184 138 1.3 29.3 128.2 199 71 PI3K delta IC₅₀ [nM] 25 39 19 18 468 6 10 83 70 46 Example 167 4.1 146.4 145.1 19 223 2.5 1.4 175.1 25.3 PI3K delta IC₅₀ [nM] 72 14 29 6 5 31 7 432 199 16 Example 98.3 122 224.1 221.1 118.5 12 150.2 2.1 96 33 PI3K delta IC₅₀ [nM] 6 27 10 30 22 8 82 14 43 0 Example 189 29.1 162 31 155.2 187 41 248.5 23.2 204 PI3K delta IC₅₀ [nM] 318 19 22 18 3 11 211 39 17 42 Example 79 2.7 169.1 186 16.5 215.2 213.2 242.2 250 28.3 PI3K delta IC₅₀ [nM] 8 33 13 26 23 22 7 6 6 292 Example 147 166.5 144.1 102 170 128.1 38 4.2 28.1 46 PI3K delta IC₅₀ [nM] 6 29 94 61 27 17 8 30 <3 <3 Example 166.3 35 100 1.2 169.2 244 149.2 245 240 234.3 PI3K delta IC₅₀ [nM] 14 169 810 115 228 3 17 6 371 11 Example 215.1 1.7 11 18 3.11 248.2 87.4 56.4 50 155.4 PI3K delta IC₅₀ [nM] 39 18 70 82 4 17 29 <3 147 32 Example 148.2 16.2 177.2 222 248.1 149.1 72 234.2 106 6.2 PI3K delta IC₅₀ [nM] 10 19 6 453 9 26 37 39 7 3 Example 25.5 109 56.1 51.2 129 254 154.1 81.1 75 166.1 PI3K delta IC₅₀ [nM] 4 42 10 93 10 3 20 28 178 13 Example 84.1 30.2 87.1 53.2 242.1 39 124 152.2 47 148.3 PI3K delta IC₅₀ [nM] 4 449 4 8 17 5 431 7 14 8 Example 188 37.1 165 88.2 156 1.8 3.10 166.2 146.3 161 PI3K delta IC₅₀ [nM] 60 27 30 161 38 5 17 21 10 12 Example 232 16.3 2.3 16.4 149.3 17.3 27.1 226 1.10 58.4 PI3K delta IC₅₀ [nM] 18 46 5 5 362 54 34 7 167 7 Example 142.3 85.3 215.3 84.2 51.5 2.9 14 236 8.1 34 PI3K delta IC₅₀ [nM] <3 8 35 257 9 6 20 18 <3 7 Example 169.3 220.1 197.1 15.1 141.3 180.2 180.1 121 248.4 152.3 PI3K delta IC₅₀ [nM] 34 26 14 35 203 6 32 3 116 41 Example 3.8 227 195.1 195.2 91 87.3 25.2 168.3 21.1 224.2 PI3K delta IC₅₀ [nM] 43 19 4 9 26 21 19 39 <3 7 Example 74 54.1 58.2 237 90.2 148.1 118.4 58.5 93.1 243 PI3K delta IC₅₀ [nM] <3 6 35 14 36 4 821 80 85 7 Example 160.1 86.2 87.5 211.1 69 45.2 15.2 154.2 178 6.3 PI3K delta IC₅₀ [nM] 8 15 91 53 13 41 23 34 15 215 Example 158.2 23.1 59.1 28.2 210 93.2 174 43.2 2.8 57 PI3K delta IC₅₀ [nM] 158 15 473 12 132 214 209 9 6 42 Example 3.6 176 238 205 55 136 112 209 185.2 110 PI3K delta IC₅₀ [nM] 9 20 38 694 8 10 3 556 691 25 Example 185.1 63 17.2 60.2 77 155.3 76 108 213.1 16.1 PI3K delta IC₅₀ [nM] 218 112 22 Example 43.1 3.9 153.3 PI3K gamma IC₅₀ [nM] 82 386 246 415 283 390 213 307 303 777 Example 34 17.1 3.1 16.1 45 2.5 51.1 74 25 68 PI3K gamma IC₅₀ [nM] 140 150 212 287 191 147 69 453 253 319 Example 32.1 30.2 251 100 7.2 107 29.1 68 58.4 6.2 PI3K gamma IC₅₀ [nM] 118 160 100 212 184 157 217 190 242 178 Example 31 32.2 1.9 14 121 54.1 2.7 53.1 4.2 30.1 PI3K gamma IC₅₀ [nM] 341 391 205 179 83 529 199 337 528 292 Example 72 21.2 2.8 59.1 40 3.8 56.2 110 15.1 4.5 PI3K gamma IC₅₀ [nM] 309 185 182 144 121 129 489 125 157 114 Example 5.1 250 6.1 1.8 127 10.2 16.2 249 1.6 43.2 PI3K gamma IC₅₀ [nM] 121 113 95 96 123 128 138 118 238 150 Example 56.4 35 58.1 76 38 33 51.2 36 1.10 4.9 PI3K gamma IC₅₀ [nM] 138 160 92 73 165 132 111 150 145 169 Example 101 23 12 22 41 1.5 24 43.1 254 29.3 PI3K gamma IC₅₀ [nM] 286 144 236 227 194 540 246 356 357 197 Example 109 37.1 116 5.2 28.3 1.3 102 66 3.5 57 PI3K gamma IC₅₀ [nM] 646 341 481 388 182 597 225 120 408 407 Example 69 4.4 4.6 46 3.6 52 117 1.7 16.3 4.1 PI3K gamma IC₅₀ [nM] 206 278 137 216 873 343 701 590 237 199 Example 2.9 49 27.2 1.2 17.2 55 47 42 44 2.4 PI3K gamma IC₅₀ [nM] 559 471 582 257 250 397 867 760 971 173 Example 3.2 112 104 56.3 91 18 3.10 48 19 123 PI3K gamma IC₅₀ [nM] 334 359 851 309 788 273 535 325 310 777 Example 50 16.3 115 3.3 2.6 10.1 108 15.3 105 26 PI3K gamma IC₅₀ [nM] 816 183 142 75 191 75 117 45 138 123 Example 63 53.2 128.1 28.1 103.1 39 128.2 252 118.3 56.1 PI3K gamma IC₅₀ [nM] 142 140 335 548 164 174 363 303 118 145 Example 4.3 2.1 37.2 15.2 118.1 28.2 125.1 3.7 124 29.2 PI3K gamma IC₅₀ [nM] 215 88 116 87 279 75 Example 27.1 253 120 13 118.2 77

The efficacy of the compounds of formula I and salts thereof as mTor kinase inhibitors can be demonstrated as follows

Biochemical Assay for m-TOR by TR-FRET.

Assay components are purchased from Invitrogen Corporation (Carlsbad/CA, USA): GFP-4EBP1 (Cat. No. PV4759), Tb3+-α-p4EBP1 [pThr46] Antibody (Cat. No. PV4757), proprietary TR-FRET dilution buffer (Cat. No. PV3574), mTOR protein (Cat. No. PV4753).

50 nL of compound dilutions (final concentration of 10, 3.0, 1.0, 0.3, 0.1, 0.03, 0.01 and 0.003 μM) are dispensed onto black 384-well low volume non-binding polystyrene (Cat. No. NBS#3676, Corning, Lowell, Mass., USA). Then 5 μL of ATP (8 μM final concentration) and GFP-4EBP1 (400 nM final concentration) with 5 μL mTOR proteins (0.5 nM final concentration) are incubated at rt. The standard reaction buffer for the TR-FRET mTOR assay contained 50 mM HEPES pH 7.5, 10 mM MnCl2, 50 mM NaCl, 1 mM EGTA, 1 mM DTT. Reactions were stopped with 10 μL of a mixture of EDTA containing the Tb3+-α-p4EBP1-[pT46] detection Ab (0.5 nM) in TR-FRET dilution buffer (proprietary to IVG). Plates are read 15 mins later in a Synergy2 reader using an integration time of 0.2 seconds and a delay of 0.1 seconds. Control for the 100% inhibition of the kinase reaction is performed by replacing the mTOR kinase by the standard reaction buffer. The control for the 0% inhibition is given by the solvent vehicle of the compounds (90% DMSO in H2O). A standard compound is used as a reference compound and included in all assay plates in the form of 16 dilution points in duplicate.

The range of activity, expressed as IC₅₀, in this assay is preferably between 1 nM and 5000 nM, more preferably between 1 nM and about 1000 nM.

mTOR IC₅₀ [nM] <3 672 5 21 174 210 22 15 22 <3 Example 164 106 120 209 238 149.3 98.3 248.3 4.5 79 mTOR IC₅₀ [nM] 82 7 15 92 12 91 135 96 <3 13 Example 25.6 45.3 178 212.2 148.3 121 250 59.1 165 15.1 mTOR IC₅₀ [nM] 11 94 97 778 3 28 1821 3 101 677 Example 51.1 54.2 126 29.2 89 247.3 170 144.3 194.1 8.2 mTOR IC₅₀ [nM] 19 6 4 8 30 17 30 34 4 15 Example 175.3 182 43.2 88.1 249 189 74 16.1 158.2 4.2 mTOR IC₅₀ [nM] 95 12 9 161 13 <3 43 70 14 152 Example 148.1 155.2 25.1 227 5.2 87.2 6.2 237 110 25.2 mTOR IC₅₀ [nM] 15 <3 123 5 11 14 76 20 191 347 Example 203 99 18 127 109 234.1 195.3 112 3.6 2.2 mTOR IC₅₀ [nM] 56 6 10 179 112 512 17 5 <3 27 Example 232 25.4 1.6 72 26 91 234.3 155.3 161 141.3 mTOR IC₅₀ [nM] 9 12 639 34 58 9 147 71 481 231 Example 146.3 158.3 69 247.4 167 2.5 246 40 142.1 46 mTOR IC₅₀ [nM] 542 3 133 10 5 132 30 703 642 52 Example 231 58.2 34 157 90.1 1.3 64 60.2 62 56.2 mTOR IC₅₀ [nM] 160 3 5 <3 548 7 5 49 68 58 Example 73 87.1 156 180.2 3.12 208 129 27.1 17.2 242.1 mTOR IC₅₀ [nM] 18 7 3 24 140 31 5 25 139 3 Example 5.1 23.2 158.5 224.2 135 243 41 191.1 219 162 mTOR IC₅₀ [nM] 120 16 20 6 11 45 21 51 48 11 Example 80.2 56.4 98.1 248.4 4.9 196.1 139 125.1 10.2 147 mTOR IC₅₀ [nM] <3 479 373 113 <3 27 3 6 172 <3 Example 185.1 146.6 213.1 143 144.2 82 200 142.2 145.1 168.3 mTOR IC₅₀ [nM] 72 10 110 470 505 7 69 678 13 207 Example 212.1 252 33 117 4.7 97 128.1 148.4 133 66 mTOR IC₅₀ [nM] 60 363 16 32 <3 14 14 4 28 4 Example 108 27.2 166.4 220.2 236 1.10_(—) 58.1 158.1 32.1 173 mTOR IC₅₀ [nM] 329 34 <3 6 56 118 26 79 6 162 Example 85.3 7.2 160.1 184 221.2 93.2 59.2 54.1 16.5 2.6 mTOR IC₅₀ [nM] 34 19 113 155 11 5 12 15 322 55 Example 206.1 185.2 248.1 1.2 211.2 60.1 17.3 56.1 57 166.3 mTOR IC₅₀ [nM] 20 105 666 33 9 <3 33 41 157 Example 146.2 251 16.4 6.4 118.3 214 87.3 166.1 168.2 50 mTOR IC₅₀ [nM] 12 213 25 48 11 274 5 <3 <3 447 Example 128.2 37.1 160.2 195.1 102 144.1 6.3 172 43.1 141.1 mTOR IC₅₀ [nM] 8 99 16 7 <3 143 <3 105 17 934 Example 187 51.4 28.1 141.2 119 131 171 7.1 85.1 132 mTOR IC₅₀ [nM] 462 5 129 26 42 95 19 193 9 33 Example 68 152.2 90.2 225 4.6 105 37.3 196.2 148.2 2.8 mTOR IC₅₀ [nM] 20 6 5 25 29 149 151 13 45 201 Example 95 100 220.3 55 87.5 169.2 2.9 28.3 16.3 21.1 mTOR IC₅₀ [nM] 309 564 563 16 48 79 60 161 52 4 Example 146.4 71 44 145.2 146.5 240 107 3.4 30.1 118.2 mTOR IC₅₀ [nM] 58 9 <3 10 34 7 9 23 383 27 Example 65 215.2 223 125.2 224.1 45.1 136 58.5 9 51.6 mTOR IC₅₀ [nM] 35 54 22 4 3 734 6 99 30 <3 Example 215.1 30.2 103.2 118.4 155.1 8.1 194.2 247.5 6.1 77 mTOR IC₅₀ [nM] 565 30 61 155 335 11 65 26 324 10 Example 248.5 98.2 83 175.2 15.2 207 61 29.1 137 138 mTOR IC₅₀ [nM] 46 15 10 15 49 100 30 448 432 13 Example 49 116 181 151 239 134 4.1 2.4 25.5 179 mTOR IC₅₀ [nM] 51 8 27 13 6 6 87 59 96 566 Example 35 150.2 201 88.2 1.8 38 96 17.1 2.3 58.3 mTOR IC₅₀ [nM] 324 79 53 17 22 6 121 12 12 <3 Example 81.2 149.1 104 3.5 205 175.1 22 247.2 199 101 mTOR IC₅₀ [nM] <3 22 87 619 107 31 65 465 69 4 Example 51.2 222 195.2 154.1 53.1 58.4 254 230 39 81.1 mTOR IC₅₀ [nM] 98 21 4 76 6 177 <3 39 <3 189 Example 153.1 193 84.1 245 51.3 31 153.2 197.1 183 152.3 mTOR IC₅₀ [nM] 61 232 549 7 107 56 11 7 9 13 Example 1.5 123 28.2 174 197.2 186 3.1 215.3 3.8 80.1 mTOR IC₅₀ [nM] 23 308 260 <3 41 77 3 100 15 39 Example 16.2 1.9 75 188 218 87.4 253 4.4 176 149.2 mTOR IC₅₀ [nM] 4 <3 543 74 79 36 251 5 27 79 Example 23.1 36 4.3 52 241 140.1 4.8 180.1 220.1 244 mTOR IC₅₀ [nM] 31 7 13 12 17 87 22 40 17 169 Example 86.2 29.3 247.1 168.1 150.1 1.4 155.4 210 12 226 mTOR IC₅₀ [nM] 17 70 6 494 3 763 24 12 <3 <3 Example 142.3 158.4 14 130 177.1 56.5 45.2 15.3 146.1 93.1 mTOR IC₅₀ [nM] <3 64 6 81 63 10 34 <3 4 5 Example 118.5 233 192 70 13 234.2 191.2 169.1 216 122 mTOR IC₅₀ [nM] 651 23 12 <3 13 5 187 123 376 55 Example 3.3 3.7 217 163 211.1 118.1 234.4 213.2 92 166.2 mTOR IC₅₀ [nM] 12 116 6 21 65 8 37 13 13 <3 Example 159 25.3 86 103.1 42 195.4 190 215.4 152.1 169.3 mTOR IC₅₀ [nM] 19 13 29 37 15 306 665 281 11 18 Example 84.2 2.7 202 24 248.2 63 153.3 47 3.9 3.10 mTOR IC₅₀ [nM] 53 5 32 73 Example 124 76 221.1 198

The efficacy of the compounds of the invention in blocking the activation of the PI3K/PKB pathway was demonstrated in cellular settings using a reverse protein array assay for sensitive quantification of compound of formula I mediated inhibition of PKB Ser473 phosphorylation in Rat1 cells stably transfected with activated versions of PI3-kinase isoforms alpha, beta or delta:

Cells and Cell Culture Conditions:

Rat1 cell lines stably expressing a myr-HA-tagged, constitutively active subunit of the catalytic PI3K class I p110 isoform α, β or δ (addition of a myristylation signal at the N-terminus of p110 isoforms has been shown to lead to constitutive activation of PI3K and corresponding downstream signals, such as phosphorylation of PKB at Ser473) were cultivated in Dulbecco's modified Eagle's medium (DMEM high Glucose, GIBCO, cat. No. 41956-039) supplemented with 10% heat inactivated fetal bovine calf serum (Amimed, cat. No. 2-01F16-1), 1% L-Glutamine (Invitrogen, cat. No. 25030-02), 1% penicillin-streptomycin (GIBCO, cat. No. 15140-114) and 10 μg/ml Puromycine (Sigma, cat. No. P9620).

Compound Treatment of Cells and Preparation of Samples:

The Rat1-myr-HA-p110 alpha, beta and delta cells were trypsinized and counted with a CASY TT cell counter (Schärfe System GmbH, Reutlingen Germany). The cells were diluted in fresh DMEM complete medium and 3×10⁴ cells/150 μl/well seeded in 96-well TPP-tissue culture plates (TPP, cat. No. 92096). The plates were incubated at 37° C. and 5% CO₂ under humidified condition for at least 20 h. Compound of formula I working solutions were prepared freshly as serial 8 step dilutions (vol/vol) in DMSO on the day of the experiment. The working solutions were further diluted 1/500 in cell culture medium to get final compound concentrations of 10, 3.333, 1.111, 0.370, 0.123, 0.041, 0.014, 0.005 μM. The final DMSO concentration was kept constant at 0.2%. cell culture medium containing 0.2% DMSO was used as vehicle treatment control. Post incubation, the cells were treated with the serial compound dilution. 50 μl of the compound medium mixture was added to the wells containing cells and 150 μl DMEM medium and incubated for 30 minutes (37° C., 5% CO₂). After 30 minutes of incubation, the medium mixture was quickly removed by aspiration. For cell lysis, a mixture of 10% CLB1 CeLyA lysis buffer (Zeptosens, cat. No. 9000), 90% CSBL1 CeLyA spotting buffer (Zeptosens, cat. No. 9020) was freshly prepared and supplemented with 1% Octyl β-D-glucopyranoside (SIGMA, cat. No. 08001-5G) and 1 mM Na-Orthovanadate (Sigma, cat No. S-6508). 50 μl of the described lysis buffer mix was added to each well, followed by 10 minutes of incubation on ice. After an additional freeze-thaw cycle, another 50 μl of the lysis buffer mix without Octyl β-D-glucopyranoside was added to the wells, and 90 μl of the cell lysate was transferred to a 96-well V-bottom plate (Fisher Scientific, cat. No. 6067Y), followed by a centrifugation step (5 min, 1500 rpm at 19° C. in an Eppendorf 5810R centrifuge) to remove the unlysed cell debris.

Spotting of the ZeptoMARK® Chips:

The samples were spotted onto ZeptoMARKt PWG protein microarray chips (Zeptosens, Witterswil, Switzerland) with the piezoelectric microdispense-based, non-contact Nano-Plotter 2.1 (GeSiM, Grosserkmannsdorf, Germany). Each sample was spotted at 4 different sample concentrations (d1=100%, d2=75%, d3=50%, d4=25%) by diluting the cell lysate with the corresponding volume of lysis buffer mix. After spotting the ZeptoMARK® protein microarrays, the chips are incubated for 1 hour at 37° C. To receive a uniform blocking result, the CeLyA blocking buffer BB1 (Zeptosens, cat. No. 9040) is administered via an ultrasonic nebulizer. After 20 minutes of blocking the chips are extensively rinsed with deionized water (Milli-Q quality, 18MΩ×cm) and dried in a nitrogen air flow.

ZeptoREADER Signal Detection and Data Analysis:

After the sample spotting and blocking procedure, the ZeptoMARK® chips were transferred to the ZeptoCARRIER (Zeptosens, cat. No. 1100), whose six flow cells individually address the six arrays on a chip, and washed twice with 200 μl CAB1 CeLyA assay buffer (Zeptosens, cat. No. 9032). The assay buffer was then aspirated and each compartment incubated with 100 μl of the primary target antibody (pAkt Ser473; CST#9271) at RT over night. Post incubation, the primary antibody was removed, the arrays washed twice with CAB1 buffer and further incubated with 100 μl of Alexa fluor 647-labeled anti rabbit IgG Fab fragments (Invitrogen; #Z25305) for one hour at RT in the dark. After incubation, the arrays were washed twice with 200 μl CAB1 buffer. The fluorescence of the target-bound Fab fragments is read out on the ZeptoReader (Zeptosens, Witterswil, Switzerland) using a laser (excitation wavelength 635 nm) and a CCD camera. The fluorescence signal was assessed with exposure times of 1, 3, 5 and 10 seconds, depending on the intensity of the signal. The resulting four images taken per array are stored as 16-bit TIF files.

The fluorescence images for each array were analyzed with the ZeptoVIEW Pro 2.0 software (Zeptosens, Witterswil, Switzerland) and the relative fluorescence intensity for each signal was calculated. The range of activity, expressed as IC₅₀, in this assay is preferably between about 1 nM and about 10 μM, more preferably between about 1 nM and about 1 μM.

Rat1-myr-p110 alpha p-PKB IC₅₀ [nM] 51 17 9 41 264 383 50 21 129 134 38 Example 132 27.1 174 250 78 58.3 10.2 151 196.2 108 166.2 p-PKB IC₅₀ [nM] 7 25 139 30 <5 150 <5 253 136 14 8 Example 249 25.3 18 30.1 161 141.1 146.1 154.2 227 5.2 193 p-PKB IC₅₀ [nM] 14 5 23 7 552 72 197 <5 371 151 46 Example 43.1 29.1 202 97 2.1 240 83 87.3 242.2 148.4 1.3 p-PKB IC₅₀ [nM] 344 <5 45 <5 9 33 33 30 88 7 8 Example 175.3 144.3 196.1 94 58.2 87.4 102 254 155.4 28.1 51.3 p-PKB IC₅₀ [nM] 35 20 <5 12 55 70 21 82 20 28 352 Example 3.5 168.1 84.1 98.3 109 146.4 58.1 1.7 178 15.3 15.2 p-PKB IC₅₀ [nM] 13 9 65 7 168 36 47 35 6 12 166 Example 99 1.8 207 103.2 22 138 65 39 220.3 64 67 p-PKB IC₅₀ [nM] 5 32 143 9 244 <5 206 7 <5 128 26 Example 36 6.2 93.2 28.3 92 153.2 75 159 163 3.12 45.2 p-PKB IC₅₀ [nM] 44 <5 29 5 22 124 234 7 17 18 <5 Example 247.4 122 31 166.4 1.1 177.2 91 5.1 234.4 2.5 160.1 p-PKB IC₅₀ [nM] <5 175 324 <5 16 <5 60 846 14 11 6 Example 146.2 247.3 137 180.1 215.1 118.5 45.1 56.5 51.4 206.1 142.2 p-PKB IC₅₀ [nM] 13 96 25 10 12 8 <5 63 18 <5 50 Example 155.1 66 58.4 142.3 100 25.6 186 195.1 221.2 116 29.2 p-PKB IC₅₀ [nM] <5 26 10 <5 138 43 115 <5 53 73 45 Example 93.1 144.1 168.3 241 34 215.2 212.2 118.4 4.4 17.1 3.6 p-PKB IC₅₀ [nM] 47 9 50 30 192 <5 6 5 <5 26 38 Example 103.1 6.3 3.3 4.6 8.2 148.2 187 155.2 248.1 233 185.2 p-PKB IC₅₀ [nM] 8 95 14 7 23 162 17 51 49 214 28 Example 188 54.1 27.2 152.1 199 33 90.2 57 149.3 46 2.7 p-PKB IC₅₀ [nM] 191 107 9 <5 20 265 10 14 24 208 10 Example 21.1 118.3 177.1 148.3 74 63 1.6 191.1 3.1 115 111 p-PKB IC₅₀ [nM] 44 180 13 10 5 134 8 16 46 44 77 Example 2.9 76 23.1 203 4.9 4.7 204 4.1 2.8 194.1 197.2 p-PKB IC₅₀ [nM] 5 6 37 282 104 <5 125 123 <5 6 102 Example 25.1 165 71 117 224.2 95 213.1 152.3 164 52 154.1 p-PKB IC₅₀ [nM] 1 55 33 63 26 13 141 166 285 227 <5 Example 79 222 86.2 148.1 1.9 215.3 126 72 214 246 89 p-PKB IC₅₀ [nM] 59 14 9 10 74 187 12 159 <5 28 <5 Example 175.2 4.2 172 156 16.1 85.2 51.6 2.2 128.2 247.1 144.2 p-PKB IC₅₀ [nM] 52 25 45 82 829 16 33 <5 126 40 7 Example 139 15.1 242.1 125.2 60.2 173 1.2 157 206.2 166.3 77 p-PKB IC₅₀ [nM] 21 8 8 23 76 32 375 13 85 77 13 Example 129 118.1 86 183 205 238 53.2 234.2 107 105 81.1 p-PKB IC₅₀ [nM] 108 29 19 13 9 75 51 65 23 120 8 Example 217 140.2 153.1 61 171 125.1 49 2.4 197.1 3.2 35 p-PKB IC₅₀ [nM] 12 18 214 10 26 <5 5 68 21 279 26 Example 2.3 179 3.4 216 135 1.10 127 4.3 17.3 229 14 p-PKB IC₅₀ [nM] 42 6 44 7 20 157 41 375 14 61 98 Example 54.2 43.2 30.2 158.2 215.4 142.1 131 21.2 7.2 6.1 37.1 p-PKB IC₅₀ [nM] 9 22 <5 44 14 10 304 20 11 24 730 Example 145.2 1.4 155.3 82 45.3 3.9 56.3 208 211.1 112 245 p-PKB IC₅₀ [nM] 97 80 18 5 126 69 <5 28 71 41 36 Example 25.5 149.2 253 184 59.1 145.1 141.2 198 104 44 243 p-PKB IC₅₀ [nM] <5 10 51 19 17 9 77 28 <5 237 22 Example 189 220.1 181 169.3 51.5 194.2 40 239 236 87.5 166.1 p-PKB IC₅₀ [nM] 172 <5 221 237 19 36 <5 114 52 337 268 Example 146.6 118.2 32.2 3.11 190 42 248.4 158.4 219 73 170 p-PKB IC₅₀ [nM] 40 57 594 15 35 10 <5 10 9 27 20 Example 143 210 10.1 182 167 141.3 60.1 234.1 150.1 169.1 146.3 p-PKB IC₅₀ [nM] 20 <5 <5 108 755 13 5 589 84 32 18 Example 195.4 88.1 200 80.2 69 185.1 128.1 8.1 140.1 251 209 p-PKB IC₅₀ [nM] <5 <5 <5 18 254 158 11 78 6 85 6 Example 84.2 85.1 90.1 237 121 4.8 23.2 24 119 32.1 158.1 p-PKB IC₅₀ [nM] <5 9 27 14 <5 8 296 42 828 7 15 Example 51.1 56.4 191.2 221.1 162 211.2 85.3 6.4 247.5 150.2 51.2 p-PKB IC₅₀ [nM] <5 22 59 48 92 135 12 90 48 73 16 Example 98.1 218 3.10 195.2 195.3 212.1 96 25.2 41 47 56.1 p-PKB IC₅₀ [nM] 8 10 818 15 12 <5 301 72 8 303 115 Example 16.5 98.2 113 3.8 59.2 87.2 166.5 50 29.3 114 244 p-PKB IC₅₀ [nM] 159 9 19 15 7 34 <5 20 220 37 67 Example 26 248.3 224.1 234.3 38 153.3 158.3 55 81.2 12 16.3 p-PKB IC₅₀ [nM] 58 67 12 <5 12 13 53 80 11 151 469 Example 213.2 110 192 25.4 146.5 80.1 58.5 225 223 16.2 62 p-PKB IC₅₀ [nM] 19 15 24 17 11 31 12 303 40 19 22 Example 17.2 53.1 88.2 175.1 136 149.1 201 56.2 37.3 220.2 4.5 p-PKB IC₅₀ [nM] 43 <5 76 45 <5 16 12 460 234 <5 17 Example 3.7 180.2 28.2 247.2 176 1.5 252 169.2 16.4 87.1 147 p-PKB IC₅₀ [nM] <5 141 12 330 Example 152.2 2.6 168.2 130

Rat1-myr-p110 beta p-PKB IC₅₀ [nM] 63 7 386 <5 21 141 86 21 49 5 84 Example 207 155.2 244 153.2 55 2.9 66 27.1 144.1 156 149.3 p-PKB IC₅₀ [nM] <5 38 17 36 9 173 25 89 6 24 88 Example 43.2 211.2 95 45.3 52 21.1 168.1 109 236 64 158.4 p-PKB IC₅₀ [nM] 21 111 22 114 6 24 14 207 118 38 37 Example 179 225 86 195.1 148.2 169.3 58.2 148.4 135 2.7 175.1 p-PKB IC₅₀ [nM] 153 196 <5 70 22 37 77 18 64 41 87 Example 34 80.2 200 16.2 209 169.1 197.2 81.1 251 2.8 247.2 p-PKB IC₅₀ [nM] 168 13 16 22 308 7 10 72 38 135 15 Example 145.1 141.3 177.1 5.2 115 23.1 35 167 138 37.1 234.3 p-PKB IC₅₀ [nM] 52 30 <5 725 9 148 185 223 13 93 11 Example 6.4 103.1 118.5 32.2 127 22 212.2 206.1 203 29.1 142.2 p-PKB IC₅₀ [nM] 386 23 <5 22 <5 275 386 16 34 11 220 Example 2.4 1.5 162 210 118.4 229 245 215.3 186 43.1 227 p-PKB IC₅₀ [nM] 196 16 <5 389 41 72 428 52 937 29 <5 Example 47 99 171 27.2 105 4.6 137 247.1 10.1 131 118.2 p-PKB IC₅₀ [nM] 659 497 119 45 245 37 171 6 55 189 13 Example 117 219 3.6 243 154.2 96 67 85.1 233 195.2 80.1 p-PKB IC₅₀ [nM] 634 52 92 22 22 66 51 18 110 86 8 Example 53.2 183 54.1 155.1 151 149.1 3.7 182 32.1 166.2 1.8 p-PKB IC₅₀ [nM] 795 20 6 124 15 <5 8 9 8 295 13 Example 2.1 252 152.1 24 29.3 141.2 248.4 146.1 84.1 81.2 172 p-PKB IC₅₀ [nM] 98 29 139 265 <5 139 8 115 240 8 8 Example 125.1 173 58.4 59.1 87.1 148.1 88.1 25.5 247.3 159 5.1 p-PKB IC₅₀ [nM] 29 160 11 57 7 64 383 16 10 31 457 Example 56.1 193 56.4 17.1 176 39 75 136 90.2 84.2 226 p-PKB IC₅₀ [nM] 40 25 6 586 20 18 11 16 15 18 14 Example 17.2 248.3 168.3 169.2 221.1 14 150.1 184 6.3 2.5 118.1 p-PKB IC₅₀ [nM] 266 766 29 59 110 12 48 43 38 548 81 Example 205 85.3 202 224.1 4.4 144.2 215.1 118.3 192 3.3 248.1 p-PKB IC₅₀ [nM] 42 6 <5 97 356 6 <5 110 13 22 113 Example 44 25.1 90.1 250 76 4.9 160.1 71 111 1.6 110 p-PKB IC₅₀ [nM] 28 10 96 68 516 <5 6 46 37 36 16 Example 61 16.5 1.3 149.2 62 87.2 158.2 185.1 41 140.2 129 p-PKB IC₅₀ [nM] 47 407 386 85 37 18 231 9 417 127 161 Example 155.4 87.5 78 87.4 187 168.2 18 51.3 73 146.4 175.2 p-PKB IC₅₀ [nM] 22 14 715 959 136 29 428 154 <5 30 299 Example 17.3 103.2 92 206.2 2.6 28.1 146.6 4.8 163 58.1 72 p-PKB IC₅₀ [nM] 6 94 88 12 26 <5 157 128 29 23 38 Example 23.2 239 185.2 204 254 161 1.4 240 146.5 3.8 30.1 p-PKB IC₅₀ [nM] 20 57 26 19 510 273 6 43 130 119 23 Example 3.1 143 234.2 4.1 3.11 21.2 220.3 65 224.2 213.2 60.1 p-PKB IC₅₀ [nM] 108 70 199 37 166 116 113 103 22 15 444 Example 196.2 3.10 212.1 104 3.12 2.3 1.9 221.2 122 25.6 121 p-PKB IC₅₀ [nM] 17 21 59 28 29 342 995 119 92 49 13 Example 234.1 15.1 234.4 88.2 3.5 213.1 242.2 146.3 68 31 98.1 p-PKB IC₅₀ [nM] 18 61 125 9 55 725 8 16 176 17 10 Example 116 59.2 28.2 38 153.3 114 77 253 70 153.1 152.2 p-PKB IC₅₀ [nM] 81 66 <5 26 6 16 73 409 99 103 19 Example 194.1 1.1 189 199 128.2 98.3 25.3 56.2 132 196.1 3.9 p-PKB IC₅₀ [nM] 52 58 30 <5 265 65 300 35 58 121 17 Example 222 10.2 147 180.1 126 40 142.1 7.2 191.2 4.7 97 p-PKB IC₅₀ [nM] 19 391 541 530 6 39 106 235 284 22 41 Example 142.3 91 46 15.2 51.2 16.3 57 37.3 82 249 247.4 p-PKB IC₅₀ [nM] 17 17 55 53 744 152 40 38 11 49 128 Example 158.1 4.5 237 86.2 63 49 197.1 12 146.2 178 108 p-PKB IC₅₀ [nM] 32 9 104 <5 353 692 101 47 248 17 43 Example 180.2 93.1 154.1 241 83 175.3 107 6.2 3.4 208 53.1 p-PKB IC₅₀ [nM] 187 39 80 615 <5 10 37 <5 <5 113 27 Example 125.2 139 45.1 4.3 1.10 174 198 164 51.1 215.2 218 p-PKB IC₅₀ [nM] 10 21 184 162 19 <5 516 143 294 10 553 Example 194.2 1.2 195.3 141.1 201 144.3 85.2 29.2 246 150.2 2.2 p-PKB IC₅₀ [nM] 10 100 66 214 15 226 136 18 608 94 11 Example 148.3 140.1 42 33 28.3 26 215.4 220.1 214 242.1 165 p-PKB IC₅₀ [nM] 54 494 73 43 119 <5 281 7 24 138 13 Example 181 177.2 112 30.2 50 155.3 58.3 79 223 3.2 145.2 p-PKB IC₅₀ [nM] 8 116 56 43 22 6 34 61 161 10 12 Example 157 238 74 54.2 188 36 16.1 211.1 217 119 51.6 p-PKB IC₅₀ [nM] 14 11 119 19 113 11 57 27 102 <5 326 Example 100 94 166.3 4.2 152.3 166.4 216 128.1 58.5 158.3 8.2 p-PKB IC₅₀ [nM] 36 54 21 <5 147 23 43 370 32 18 34 Example 45.2 191.1 15.3 87.3 1.7 195.4 6.1 170 220.2 98.2 102 p-PKB IC₅₀ [nM] 16 7 <5 54 Example 190 25.4 89 166.1

Rat1-myr-p110 delta p-PKB IC₅₀ [nM] 140 5 7 24 399 56 15 516 37 298 28 Example 1.3 153.2 164 146.1 33 216 51.3 51.5 3.8 67 16.5 p-PKB IC₅₀ [nM] 564 19 8 88 141 323 131 266 54 13 72 Example 146.6 38 248.4 191.2 154.1 80.2 240 126 190 236 192 p-PKB IC₅₀ [nM] 810 69 59 9 5 53 10 356 26 10 59 Example 69 225 4.1 155.3 189 210 118.2 63 23.1 160.1 29.1 p-PKB IC₅₀ [nM] 154 15 92 84 38 58 15 86 19 18 508 Example 45.1 150.2 41 144.1 4.5 138 88.1 58.4 142.2 146.2 27.2 p-PKB IC₅₀ [nM] 234 238 71 401 906 10 177 140 90 45 297 Example 29.2 207 68 108 21.1 201 75 1.9 6.1 28.1 219 p-PKB IC₅₀ [nM] 636 30 127 202 433 9 471 158 869 11 21 Example 247.3 234.3 131 34 226 241 93.2 185.2 169.2 144.3 141.2 p-PKB IC₅₀ [nM] 634 530 9 11 882 25 22 219 42 115 69 Example 87.5 73 25.1 56.4 2.4 95 51.2 37.1 145.2 215.4 59.2 p-PKB IC₅₀ [nM] 839 91 541 9 83 895 12 370 559 8 138 Example 47 15.1 2.2 25.4 208 242.2 157 148.4 177.2 36 40 p-PKB IC₅₀ [nM] 672 38 833 314 249 130 341 64 772 577 362 Example 53.2 29.3 166.5 18 1.7 16.1 121 31 205 58.3 37.3 p-PKB IC₅₀ [nM] 631 46 158 66 91 132 154 14 50 22 73 Example 91 129 42 103.1 243 197.1 224.1 1.8 168.1 77 248.1 p-PKB IC₅₀ [nM] 84 26 768 56 84 50 41 224 79 170 1630 Example 3.10 203 212.1 221.2 39 56.1 169.3 85.2 12 24 10.1 p-PKB IC₅₀ [nM] 275 280 10 22 21 15 157 44 442 12 68 Example 70 74 128.2 86 195.4 172 25.5 4.2 49 144.2 222 p-PKB IC₅₀ [nM] 473 247 43 101 24 44 118 43 7 131 5 Example 3.2 25.2 100 193 187 253 149.1 98.3 168.3 1.4 1.10 p-PKB IC₅₀ [nM] 62 946 33 32 41 91 8 363 56 450 19 Example 6.4 2.1 152.2 25.6 221.1 87.4 93.1 135 149.2 26 155.1 p-PKB IC₅₀ [nM] 137 29 57 140 547 42 74 58 25 106 12 Example 3.5 199 86.2 251 4.7 98.1 14 196.1 179 103.2 148.2 p-PKB IC₅₀ [nM] 377 133 232 <5 288 14 1508 90 8 314 41 Example 71 146.4 3.6 90.1 57 148.3 16.4 175.1 4.9 82 188 p-PKB IC₅₀ [nM] 66 178 134 276 120 119 479 41 403 66 343 Example 136 215.2 44 62 109 234.4 206.2 171 141.1 1.2 195.2 p-PKB IC₅₀ [nM] 24 103 255 196 78 62 212 66 59 50 390 Example 146.3 17.1 195.3 110 152.3 140.2 28.2 209 98.2 173 76 p-PKB IC₅₀ [nM] 749 59 58 11 30 186 56 19 235 7 631 Example 85.3 25.3 17.2 166.4 1.6 3.7 122 153.1 229 119 213.1 p-PKB IC₅₀ [nM] 157 16 86 211 366 51 9 595 89 91 35 Example 64 79 147 3.12 32.2 183 94 137 198 167 141.3 p-PKB IC₅₀ [nM] 249 193 396 307 48 13 26 204 719 112 69 Example 217 32.1 118.3 140.1 176 155.2 234.1 59.1 245 153.3 112 p-PKB IC₅₀ [nM] 5 168 165 96 240 22 425 145 34 95 240 Example 80.1 149.3 2.9 52 227 35 117 132 116 158.4 2.3 p-PKB IC₅₀ [nM] 145 59 56 336 27 12 86 91 12 211 347 Example 194.1 88.2 27.1 197.2 194.2 174 143 30.1 156 211.1 244 p-PKB IC₅₀ [nM] 21 <5 23 85 28 132 357 837 100 30 127 Example 118.4 87.1 220.1 242.1 7.2 224.2 58.5 246 15.3 97 128.1 p-PKB IC₅₀ [nM] 46 118 40 70 213 223 7 959 90 27 44 Example 43.1 250 151 139 45.3 51.4 89 78 148.1 186 54.2 p-PKB IC₅₀ [nM] 28 33 41 151 602 412 18 7 306 382 128 Example 17.3 85.1 180.1 16.2 21.2 8.2 84.1 87.3 142.1 81.2 53.1 p-PKB IC₅₀ [nM] 154 418 280 297 927 50 205 219 360 45 43 Example 195.1 3.4 145.1 22 3.3 1.5 4.6 2.6 175.2 206.1 58.1 p-PKB IC₅₀ [nM] 22 278 81 91 13 24 116 39 21 53 468 Example 215.3 4.8 1.1 125.1 220.3 28.3 254 252 150.1 218 56.2 p-PKB IC₅₀ [nM] 29 326 49 42 56 197 106 45 <5 7 12 Example 51.1 185.1 237 3.1 182 10.2 247.4 158.1 161 200 43.2 p-PKB IC₅₀ [nM] 70 50 103 225 78 105 29 162 56 246 26 Example 169.1 3.9 223 72 102 2.8 249 105 191.1 61 233 p-PKB IC₅₀ [nM] 24 18 458 489 9 105 110 16 508 288 330 Example 6.3 23.2 154.2 46 204 211.2 104 152.1 83 247.2 215.1 p-PKB IC₅₀ [nM] 570 33 24 327 6 102 54 19 772 15 8 Example 50 60.1 180.2 238 118.5 65 55 168.2 3.11 158.2 165 p-PKB IC₅₀ [nM] 62 41 61 12 24 335 59 <5 45 36 23 Example 181 239 125.2 58.2 159 196.2 146.5 87.2 220.2 2.5 142.3 p-PKB IC₅₀ [nM] 16 39 112 27 23 28 46 59 25 11 60 Example 184 177.1 54.1 5.2 234.2 202 90.2 155.4 248.3 81.1 96 p-PKB IC₅₀ [nM] 19 85 57 12 607 157 203 18 50 62 16 Example 99 178 166.1 163 170 247.1 45.2 111 166.2 2.7 84.2 p-PKB IC₅₀ [nM] 111 15 76 155 <5 125 155 176 18 18 193 Example 166.3 51.6 6.2 4.4 158.3 16.3 30.2 66 127 5.1 107 p-PKB IC₅₀ [nM] 787 12 Example 4.3 118.1

The efficacy of the compounds of the invention in displaying an inhibitory effect downstream of mTORC1 complex (mTOR/raptor) was demonstrated in cellular setting using a reverse protein array assay for sensitive quantification of drug-mediated inhibition of S6 Ribosomal Protein phosphorylation Ser235/236 in TSC1 null mouse embryo fibroblast (MEF) cells.

Cells and Cell Culture Conditions:

TSC1−/− MEFs cells (provided by D. Kwiatkowski), were cultivated in Dulbecco's modified Eagle's medium (DMEM high Glucose, GIBCO, cat. No. 41956-039) supplemented with 10% heat inactivated fetal bovine calf serum (Amimed, cat. No. 2-01F16-1), 1% L-Glutamine (Invitrogen, cat. No. 25030-02), 1% penicillin-streptomycin (GIBCO, cat. No. 15140-114) at 37° C. in a 5% CO2 and 95% relative humidity atmosphere incubator.

Treatment of Cells and Preparation of Samples:

The TSC1−/− cells were trypsinized and counted with a CASY TT cell counter (Schirfe System GmbH, Reutlingen Germany). The cells were diluted in fresh DMEM complete medium and 0.75×10⁴ cells/150 μl/well seeded in 96-well TPP-tissue culture plates (TPP, cat. No. 92096). The plates were incubated at 37° C. and 5% CO₂ under humidified condition for at least 20 h. Working solutions were prepared freshly as serial 8 step dilutions (vol/vol) in DMSO on the day of the experiment. The working solutions were further diluted 1/5000 in cell culture medium to get final compound concentrations of 1, 0.3333, 0.1111, 0.037, 0.0123, 0.041, 0.0014, 0.005 μM. The final DMSO concentration was kept constant at 0.02%. cell culture medium containing 0.02% DMSO was used as vehicle treatment control. Post incubation, the cells were treated with the serial compound dilution. 50 μl of the compound medium mixture was added to the wells containing cells and 150 μl DMEM medium and incubated for 60 minutes (37° C., 5% CO₂). After 60 minutes of incubation, the medium mixture was quickly removed by aspiration. For cell lysis, a mixture of 10% CLB1 CeLyA lysis buffer (Zeptosens, cat. No. 9000), 90% CSBL1 CeLyA spotting buffer (Zeptosens, cat. No. 9020) was freshly prepared and supplemented with 1% Octyl β-D-glucopyranoside (SIGMA, cat. No. 08001-5G) and 1 mM Na-Orthovanadate (Sigma, cat No. S-6508). 50 μl of the described lysis buffer mix was added to each well, followed by 10 minutes of incubation on ice. After an additional freeze-thaw cycle, another 50 μl of the lysis buffer mix without Octyl 13-D-glucopyranoside was added to the wells, and 90 μl of the cell lysate was transferred to a 96-well V-bottom plate (Fisher Scientific, cat. No. 6067Y), followed by a centrifugation step (5 min, 1500 rpm at 19° C. in an Eppendorf 5810R centrifuge) to remove the unlysed cell debris.

Spotting of the ZeptoMARK® Chips:

The spotting of the chips follows the previous described method.

ZeptoREADER Signal Detection and Data Analysis:

The signal detection and the data analysis follows the previous described method using the pS6 ribosomal protein Ser235/236 (CST, cat. No. #2211) as a primary antibody.

The range of activity, expressed as IC₅₀, in this assay is preferably between about 0.1 nM

p-S6 IC₅₀ [nM] 3 60 1 6 61 31 36 4 14 46 Example 132 112 202 2.7 16.3 195.2 153.3 100 30.1 107 p-S6 IC₅₀ [nM] 30 11 1 8 39 24.99 2 15 <0.5 1 Example 37.1 15.1 25.6 25.5 215.1 51.5 88.1 3.6 144.3 87.2 p-S6 IC₅₀ [nM] 5 9 7 5.63 3 7 3 21 <0.5 4 Example 195.1 29.1 96 169.1 215.2 12 206.1 211.1 118.5 247.4 p-S6 IC₅₀ [nM] 1 174 3 5 1 10 7 <0.5 2 6.94 Example 118.2 58.3 247.1 77 51.2 2.5 167 43.2 28.3 149.3 p-S6 IC₅₀ [nM] 6 3.56 10 2.66 2 4 35 23 5 <5 Example 59.1 34 56.2 146.5 51.3 56.1 90.2 74 84.2 1.8 p-S6 IC₅₀ [nM] 19 8 <0.5 75 1 <5 41 78 4 46 Example 81.2 158.1 168.2 92 156 102 246 110 153.1 45.3 p-S6 IC₅₀ [nM] 666 1 17 5 13 1 11 1 5 2 Example 21.2 172 108 54.1 4.5 183 109 201 140.1 234.3 p-S6 IC₅₀ [nM] 1 3 41 <0.5 6 38 91 <5 2 5 Example 215.3 174 87.4 146.1 135 83 50 1.5 190 208 p-S6 IC₅₀ [nM] 4 3 4 1.02 43 355 37 234 111 4 Example 99 86 191.1 186 53.1 120 205 27.2 85.3 222 p-S6 IC₅₀ [nM] 2 44 3 <5 5 66 <5 <0.5 11 5 Example 199 1.9 233 253 86.2 65 28.1 25.4 51.4 118.1 p-S6 IC₅₀ [nM] 98 <0.5 20 1 <0.5 1.69 5 4 4 7 Example 62 241 152.3 148.3 142.2 81.1 79 1.1 243 88.2 p-S6 IC₅₀ [nM] 13 2 2 1.32 11 43.5 3 5 3 91.69 Example 27.1 152.1 23.2 169.3 3.8 45.1 43.1 131 136 166.5 p-S6 IC₅₀ [nM] 15 8.15 1 199 1 3 4 11 3 13 Example 4.1 188 152.2 3.4 158.2 224.1 151 229 181 250 p-S6 IC₅₀ [nM] 5 13 1 <5 3 35 50 17 1 1 Example 64 103.1 144.2 1.6 220.2 247.3 145.1 15.3 60.1 150.1 p-S6 IC₅₀ [nM] 1 13.5 17 80 32 2 33 2 1 2 Example 221.2 7.2 82 44 175.2 177.1 17.2 125.1 119 118.4 p-S6 IC₅₀ [nM] 558 77 2 31 33 <0.5 1 3 58 48 Example 32.2 206.2 194.2 195.3 251 51.6 175.1 146.3 72 52 p-S6 IC₅₀ [nM] 22 1 1 20 3 1 7 49.41 127 1 Example 203 85.1 54.2 194.1 171 141.2 197.2 213.1 47 129 p-S6 IC₅₀ [nM] 27 79 32 <0.5 4 10 46 5.53 2 3 Example 22 170 210 122 58.2 5.1 214 193 178 58.5 p-S6 IC₅₀ [nM] 3 10 2 9 1 35 87 1 6 5.53 Example 127 13 195.4 149.1 157 223 17.1 221.1 219 147 p-S6 IC₅₀ [nM] 1 4 278 6 5 36 130 1 <0.5 2 Example 166.4 139 146.6 116 182 40 56.5 148.2 220.3 173 p-S6 IC₅₀ [nM] 21 22 2 7 <0.5 508 <0.5 15 181 1 Example 2.8 148.1 176 4.2 90.1 133 204 118.3 16.2 95 p-S6 IC₅₀ [nM] 3 9 32 6 6 5 7 1 11 3 Example 38 128.1 185.2 237 87.3 184 212.1 128.2 32.1 80.1 p-S6 IC₅₀ [nM] 41 1 25 1.89 11 1 <0.5 3 3 2 Example 30.2 59.2 244 187 60.2 164 168.3 154.1 98.1 209 p-S6 IC₅₀ [nM] 20 39 201 4 1 5 12 123 1 9 Example 224.2 104 247.5 29.3 234.2 192 146.4 14 155.2 247.2 p-S6 IC₅₀ [nM] 28 2 30 23 2 1 72 5 17 10.11 Example 80.2 141.3 3.7 41 4.9 150.2 45.2 51.1 180.2 234.4 p-S6 IC₅₀ [nM] 2 2 2 9 18 <0.5 7 33 33 18 Example 242.1 155.1 58.4 234.1 55 218 197.1 16.1 6.1 155.4 p-S6 IC₅₀ [nM] 36 0.94 3 2 24 1 1 6 255 <0.5 Example 142.1 145.2 166.1 84.1 10.2 155.3 168.1 25.2 3.3 89 p-S6 IC₅₀ [nM] 1 <0.5 40 88 16 <0.5 39 10 27 11 Example 1.10 36 3.1 242.2 70 215.4 154.2 179 2.9 240 p-S6 IC₅₀ [nM] 36 37 1 1 2 1 6 13 13 180 Example 91 39 142.3 239 161 93.1 140.2 16.5 71 87.5 p-S6 IC₅₀ [nM] 43 22 10 22 2 13.38 3 2 175 3 Example 245 207 6.4 93.2 146.2 63 42 249 3.12 149.2 p-S6 IC₅₀ [nM] 1 10 200 1 <0.5 151 3 5 9 1 Example 165 217 76 61 158.3 175.3 198 57 137 220.1 p-S6 IC₅₀ [nM] 3 98 154 217 58 17.7 5 7 8 5.33 Example 111 46 117 49 3.5 148.4 26 226 159 126 p-S6 IC₅₀ [nM] 1 9 2 <0.5 125 10 5 2 12 11 Example 189 24 144.1 200 196.2 196.1 252 163 227 211.2 p-S6 IC₅₀ [nM] 3 3 2 2.26 15 58 1 8 4 5 Example 103.2 17.3 35 166.2 37.3 254 56.4 6.2 225 3.9 p-S6 IC₅₀ [nM] <0.5 844 3 5 5 10 <0.5 5 2 34 Example 216 37.4 138 191.2 166.3 3.10 160.1 5.2 25.3 141.1 p-S6 IC₅₀ [nM] 5 9 8 3 4 1 6 10 35 150 Example 125.2 143 6.3 97 23.1 25.1 238 4.4 185.1 158.4 p-S6 IC₅₀ [nM] 3 Example 58.1

There are also experiments to demonstrate the antitumor activity of compounds of the formula (I) in vivo.

For example, female Harlan (Indianapolis, Ind., USA) athymic nu/nu mice with s.c. transplanted human glioblastoms U87MG tumors can be used to determine the anti-tumor activity of PI3 kinase inhibitors. On day 0, with the animals under peroral Forene® (1-chloro-2,2,2-trifluoroethyldifluormethylether, Abbot, Wiesbaden, Germany) narcosis, a tumor fragment of approximately 25 mg is placed under the skin on the animals' left flank and the small incised wound is closed by means of suture clips. When tumors reach a volume of 100 mm³, the mice are divided at random into groups of 6-8 animals and treatment commences. The treatment is carried out for a 2-3 weeks period with peroral, intravenous or intra-peritoneal administration once daily (or less frequently) of a compound of formula (I) in a suitable vehicle at defined doses. The tumors are measured twice a week with a slide gauge and the volume of the tumors is calculated.

As an alternative to cell line U87MG, other cell lines may also be used in the same manner, for example,

-   -   the MDA-MB 468 breast adenocarcinoma cell line (ATCC No. HTB         132; see also In Vitro 14, 911-15 [1978]);     -   the MDA-MB 231 breast carcinoma cell line (ATCC No. HTB-26; see         also In Vitro 12, 331 [1976]);     -   the MDA-MB 453 breast carcinoma cell line (ATCC No. HTB-131);     -   the Colo 205 colon carcinoma cell line (ATCC No. CCL 222; see         also Cancer Res. 38, 1345-55 [1978]);     -   the DU145 prostate carcinoma cell line DU 145 (ATCC No. HTB 81;         see also Cancer Res. 37, 4049-58 [1978]),     -   the PC-3 prostate carcinoma cell line PC-3 (especially         preferred; ATCC No. CRL 1435; see also Cancer Res. 40, 524-34         [1980]) and the PC-3M prostate carcinoma cell line;     -   the A549 human lung adenocarcinoma (ATCC No. CCL 185; see also         Int. J. Cancer 17, 62-70 [1976]),     -   the NCl-H596 cell line (ATCC No. HTB 178; see also Science 246,         491-4 [1989]);     -   the pancreatic cancer cell line SUIT-2 (see Tomioka et al.,         Cancer Res. 61, 7518-24 [2001]). 

What is claimed is:
 1. A compound of formula (I):

in which: R₁ is a group selected from:

wherein, the curved line indicates the bonding position to the rest of the molecule of formula (I) and the alpha position is shown by the atoms labeled with a * symbol, and R¹⁰ is C₁-C₄alkyl; R¹¹ is hydrogen or C₁-C₄alkyl or fluoroC₁-C₄alkyl; R¹² is hydrogen or C₁-C₄alkyl; R¹³ is hydrogen or C₁-C₄alkyl; R¹⁴ is C₁-C₄alkyl, 2-hydroxyethyl, methoxyethyl, hydroxycarbonylmethyl (HOC(O)CH₂—), dimethylaminocarbonylmethyl (Me₂NC(O)CH₂—), ethylmethylaminocarbonylmethyl (EtMeNC(O)CH₂—), (methoxyethyl)(methyl)aminocarbonylmethylmethyl ((MeOEt)(Me)NC(O)CH₂—), 2-azetidin-1-yl-2-oxo-ethyl, 4-morpholinecarbonylmethyl and (4-methylpiperazin-1yl)carbonylmethyl; and R¹⁵ is methyl or chloro, or R¹ is a group of formula (AB):

wherein, the curved line indicates the bonding position to the rest of the molecule of formula (I) and the alpha position is shown by the atoms labeled with a * symbol, and R¹⁶ and R¹⁷ are independently selected from same or different, unsubstituted C₁-C₄alkyl; R² is hydrogen, C₁-C₄alkyl or C₁-C₄alkenyl; R³ is unsubstituted phenyl, or phenyl substituted with one or two groups independently selected from the group consisting of halo; halo-lower alkyl; hydroxyl; amino; mono or disubstituted amino; cyclic amino; amino-lower alkyl; lower alkoxy; hydroxy-lower alkyl; hydroxy lower alkoxy; lower alkyl; cyano; cyano-lower alkyl; amidino; N-hydroxyamidino; amidino-lower alkyl; or N-hydroxyamidino-lower alkyl; sulfonyl; alkyl-substituted sulfonyl; sulfonamide; pyrrolidinesulfonyl; lower alkyl sulfonyl amino; lower alkyl sulfonylalkandiylamino; lower alkylsulfonyl-N-lower alkylamino; [1,3]dioxolo; halo-substituted [1,3]dioxolo; alkoxy carbonyl; carbamoyl; substituted carbamoyl; heterocycle; heterocyclyl lower alkyl; heteroaryl or heteroaryl lower alkyl; or R³ is indolyl, 1-methyl-2,3-dihydro-1H-indolyl, 2-oxo-2,3-dihydro-1H-indolyl, pyridyl, pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1-methyl-1H-pyrrolo[2,3-b]pyridinyl, pyrazolyl, pyrazinyl, quinolyl, 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridinyl, 2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridinyl, 2,3-Dimethyl-3H-imidazo[4,5-b]pyridinyl, 3-methyl-3H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-1H-pyrrolo[3,2-b]pyridinyl, 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazinyl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl and 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazinyl each of these heterocycle radicals being unsubstituted or substituted by one to two radicals selected from the group consisting of halo; halo-lower alkyl; hydroxyl; amino; mono or disubstituted amino; cyclic amino; substituted cyclic amino; amino-lower alkyl; alkylamino-lower alkyl; dialkylamino-loweralkyl; cycloalkylaminoalkyl; dicycloalkylaminoalkyl; alkylcycloalkylaminoalkyl; lower alkoxy; cycloalkoxy; lower-alkoxyalkyl; hydroxy-lower alkyl; hydroxy lower cycloalkyl; hydroxy lower alkoxy; alkoxy lower alkoxy; lower alkyl; cyano; cyano-lower alkyl; cyano lower cycloalkyl; amidino; N-hydroxyamidino; amidino-lower alkyl; N-hydroxyamidino-lower alkyl; nitro; carboxylic acid; substituted sulfonyl; sulfonamide; alkylsulfonylamino; alkylsulfonylalkylamino; acylamino; acyl alkyl amino; alkylcarbonylaminoalkyl; alkylaminocarbonylalkyl; alkylcarbonyl-N-alkylamino; [1,3]dioxolo; substituted [1,3]dioxolo; alkoxy carbonyl; carbamoyl; substituted carbamoyl; 1H-tetrazolyl; pyrazol; imidazole; triazole; azetidinyl; pyrrolidinyl; piperazinyl; methylpiperazinyl; ethylpiperazinyl; triazolonyl; methylimidazolyl or morpholino; R⁴, R⁵ and R⁶ are hydrogen; X is O or S; and Y is CH or N; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 wherein R¹ is selected from: 1,5-dimethyl-1H-pyrazol-4-yl, 2-ethyl-2H-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 2,5-dimethyl-2H-pyrazol-3-yl, 1-isopropyl-3-methyl-1H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl, 2,4-dimethyl-2H-pyrazol-3-yl, 1,3-dimethyl-1H-pyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl, 1-hydroxycarbonyl methyl-3-methyl-pyrazol-4-yl, 1-dimethylaminocarbonylmethyl-3-methyl-pyrazol-4-yl, 1-dimethylaminocarbonylmethyl-3,5-dimethyl-pyrazol-4-yl, 1-diethylaminocarbonylmethyl-3-methyl-pyrazol-4-yl, 1-(2-hydroxyethyl)-3-methyl-pyrazol-4-yl, 1-(2-azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl, 1-(4-morpholin)-carbonylmethyl-3-methyl-pyrazol-4-yl, 3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl, 1-methyl-3-chloro-pyrazol-4-yl, 1-(2-methoxyethyl)-3,5-dimethyl-pyrazol-4-yl and 1-N-ethyl-N-methylaminocarbonylmethyl-3-methyl-pyrazol-4-yl and 3,5-dimethyl-isoxazol-4-yl, or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 1 wherein R₃ is selected from: phenyl; hydroxyphenyl; methoxyphenyl; 3,4-dimethoxyphenyl; ethoxyphenyl; 3,4-diethoxyphenyl; iso-propoxyphenyl; methoxy ethoxy-phenyl; 3-methoxy-4-(2-methoxy ethoxy)-phenyl; fluoro-(iso-propoxy)-phenyl; 3-methoxy-4-hydroxy phenyl; fluoro-hydroxy-phenyl; hydroxy-fluoroalkyl-phenyl; 2,2-difluoro-benzo[1,3]dioxolo; benzene sulfonamide; N,N-dimethylbenzenesulfonamide; 3-(pyrrolidine-1-sulfonyl)-phenyl; N-(phen-3-yl)-methanesulfonamide; N-methyl-N-phen-3-yl-methanesulfonamide; 3-methanesulfonylphenyl; 3- or 4-benzamide; 3- or 4-N-methyl-benzamide; 3- or 4-N,N-dimethyl-benzamide; pyrazol-phenyl; imidazol-phenyl; pyridyl; alkylpyridyl; alkoxypyridyl; cycloalkoxypyridyl; (haloalkoxy)pyridyl; cycloalkylalkoxypyridyl; alkoxyalkylpyridyl; alkoxyalkoxypyridyl; (alkyl)(alkoxyalkoxy)pyridyl; benzyloxyalkoxypyridyl; hydroxyalkylpyridyl; hydroxycycloalkylpyridyl; hydroxyfluoroalkylpyridyl; aminoalkylpyridyl; alkyl-sulfonyl pyridyl; hydroxyalkoxypyridyl; alkoxycarbonylpyridyl; aminopyridyl; alkylaminopyridyl; dialkylaminopyridyl; cycloalkylaminopyridyl; (N-alkyl-N-cycloalkylamino)pyridyl; (alkyl)(amino)pyridyl; (halo)(amino)pyridyl; (halo)(alkylamino)pyridyl; (halo)(dialkylamino)pyridyl; (halo)(hydroxyalkyl)pyridyl; (alkoxy)(alkyl)pyridyl; (alkoxy)(alkoxy)pyridyl; (alkoxy)(alkoxyalkyl)pyridyl; (alkoxy)(deuteroalkoxy-alkyl)pyridyl; (alkoxy)(hydroxyalkyl)pyridyl; (haloalkoxy)(alkyl)pyridyl; (haloalkoxy)(hydroxyalkyl)pyridyl; (alkoxyalkoxy)(hydroxyalkyl)pyridyl; (alkyl)(alkylamino)pyridyl; (alkyl)(di-alkylamino)pyridyl; cycloaminopyridyl; cyclic ether-substituted amino-pyridyl; hydroxy-cycloaminopyridyl; loweralkoxy-cycloaminopyridyl; hydroxyalkylaminopyridyl; (alkyl)(hydroxy)pyridyl; (hydroxyalkyl)(alkylamino)pyridyl; (hydroxyalkyl)(amino)pyridyl; (alkoxyalkyl)(alkylamino)pyridyl; (alkoxyalkyl)(amino)pyridyl; amino-haloloweralkyl-pyridyl; alkylamino-haloalkyl-pyridyl; haloalkyl-deuteroloweralkylamino-pyridyl; haloalkylpyridinyl; cyanoalkylpyridinyl; cyanocycloalkylpyridinyl; halopyridyl; halo-alkoxy-pyridyl; carbamoylpyridyl; alkyl-substituted carbamoylpyridyl; piperazinylpyridyl; N-alkylpiperazinylpyridyl; alkylsulfonamidopyridyl; dialkylsulfonamidopyridyl; (alkylsulfonamido)(alkyl)pyridyl; (alkylsulfonamido)(halo)pyridyl; (alkylsulfonamidoalkyl)pyridyl; dialkylsulfonamido(alkyl)pyridyl; 3H-tetrazol-5-yl pyridyl; alkylcarbonylaminoalkylpyridyl; (halo)(alkylcarbonylamino)pyridyl; (alkoxy)(alkylcarbonylamino)pyridyl; (alkoxy)(alkylcarbonyl-N-alkylamino)pyridyl; (alkoxy)(nitro)pyridyl; (alkoxy)(cyano)pyridyl; (alkoxy)(amino)pyridyl; (alkoxy)(alkylamino)pyridyl; (alkoxyalkyl)(alkylamino)pyridyl; (alkoxy)(alkylaminocarbonyl)pyridyl; (alkoxyalkyl)(alkylamino)pyridyl; (amino)(alkylaminocarbonyl)pyridyl; (amino)(alkoxyalkylaminocarbonyl)pyridyl; (alkylamino)(alkylaminocarbonyl)pyridyl; (alkoxy)(aminocarbonyl)pyridyl; (alkoxy)(hydroxycarbonyl)pyridyl; morpholinylpyridinyl; (1H-pyrazolyl)-pyridinyl; loweralkylsubstituted(1H-imidazol-1-yl)-pyridinyl; pyrimidinyl; di-loweralkylaminopyrimidinyl; alkoxypyrimidinyl; di-alkoxypyrimidinyl; (alkylamino)(alkoxy)pyrimidinyl; cycloaminopyrimidinyl; aminopyrimidinyl; alkylaminopyrimidinyl; dialkylaminopyrimidinyl; 1H-pyrrolo[2,3-b]pyridinyl; 1-methyl-1H-pyrrolo[2,3-b]pyridinyl; pyrazinyl; pyrazolyl; hydroxyalkylpyrazolyl; 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazolyl; quinolinyl; 2-oxo-2,3-dihydro-1H-indol-5-yl; 1-methyl-2,3-dihydro-1H-indol-5-yl; 1H-imidazo[4,5-b]pyridin-2(3H)-one-6-yl; 3H-imidazo[4,5-b]pyridin-6-yl; (3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl; (2-methyl)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl; (2-methoxy)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl; (2-dimethylamino)-(3-methyl)-3H-imidazo[4,5-b]pyridin-6-yl; 3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl; (3-methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl; H-pyrrolo[3,2-b]pyridin-6-yl; 1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl; 2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl; 1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl; 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl; 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl; 1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl; 2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl; and 1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl; or a pharmaceutically acceptable salt thereof.
 4. A compound selected from: 8-(3,4-Dimethoxy-phenyl)-1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(2-ethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(2,4-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(3,4-dimethoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,4-Dimethyl-2H-pyrazol-3-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2-Ethyl-2H-pyrazol-3-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-3-methyl-1-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-1-(2-ethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(6-Ethoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 8-(6-Ethoxy-pyridin-3-yl)-3-methyl-1-[3-methyl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrazol-4-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(6-Ethoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3,5-dimethyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 8-(6-Dimethylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Dimethylamino-pyridin-3-yl)-1-(2-ethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-dimethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Azetidin-1-yl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Azetidin-1-yl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Dimethylamino-pyrimidin-5-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Dimethylamino-pyrimidin-5-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(2-dimethylamino-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Dimethylamino-pyrimidin-5-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-methyl-8-(6-methyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-(2-methyl-2H-pyrazol-3-yl)-8-(6-trifluoromethyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-methyl-8-(6-trifluoromethyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-8-(2-fluoro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-pyridin-3-yl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Fluoro-pyridin-4-yl)-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-fluoro-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid amide; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid methylamide; 5-[3-Methyl-2-oxo-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid methylamide; 5-[1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid methylamide; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Hydroxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Hydroxymethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(2-methoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-methoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(2-methoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[6-(2-Benzyloxy-ethoxy)-pyridin-3-yl]-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[6-(3-Benzyloxy-propoxy)-pyridin-3-yl]-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[6-(2-Hydroxy-ethylamino)-pyridin-3-yl]-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-hydroxy-ethylamino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methanesulfonyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3,5-dimethyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-(3,5-dimethyl-isoxazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-trifluoromethyl-pyridin-3-yl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyrimidin-5-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Diethoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Diethoxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3-Ethoxy-4-methoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3-Ethoxy-4-methoxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-ethoxy-4-methoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(4-Ethoxy-3-methoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(4-Ethoxy-3-methoxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(4-ethoxy-3-methoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-[3-methoxy-4-(2-methoxy-ethoxy)-phenyl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(4-Hydroxy-3-methoxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-hydroxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3-Hydroxy-phenyl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-fluoro-5-hydroxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-hydroxy-5-trifluoromethyl-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-phenyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-phenyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N,N-Dimethyl-2-[3-methyl-4-(3-methyl-2-oxo-8-phenyl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-pyrazol-1-yl]-acetamide; 2-[3,5-Dimethyl-4-(3-methyl-2-oxo-8-phenyl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-quinolin-3-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-benzenesulfonamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-methanesulfonyl-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 4-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-benzamide; 8-(6-Cyclopropylmethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 4-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-benzamide; 4-[1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-benzamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-benzamide; N-{3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-phenyl}-methanesulfonamide; 4-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N,N-dimethyl-benzamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-2,3-dihydro-1H-indol-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4-pyrazol-1-yl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N,N-Dimethyl-2-{3-methyl-4-[3-methyl-2-oxo-8-(4-pyrazol-1-yl-phenyl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(4-pyrazol-1-yl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{3,5-Dimethyl-4-[3-methyl-2-oxo-8-(4-pyrazol-1-yl-phenyl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-N,N-dimethyl-acetamide; 2-{3,5-Dimethyl-4-[3-methyl-2-oxo-8-(4-pyrazol-1-yl-phenyl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-N,N-dimethyl-acetamide; N-Ethyl-N-methyl-2-{3-methyl-4-[3-methyl-2-oxo-8-(4-pyrazol-1-yl-phenyl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-ethoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N,N-dimethyl-benzenesulfonamide; N,N-Dimethyl-3-[3-methyl-2-oxo-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-benzenesulfonamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-propoxy-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(5-Ethoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 8-(5-Ethoxy-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,4-Dimethyl-2H-pyrazol-3-yl)-8-(5-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-ethoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,4-Dimethyl-2H-pyrazol-3-yl)-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-Ethyl-2-{4-[8-(5-isopropoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N-methyl-acetamide 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-[5-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Cyclobutoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(5-Cyclobutoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3,5-dimethyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 8-(5-Cyclopropylmethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-pyridin-3-yl}-N-methyl-acetamide; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-ethoxy-pyridin-3-yl}-N-methyl-acetamide; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-pyridin-3-yl}-acetamide; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-ethoxy-pyridin-3-yl}-acetamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(1-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[1-(2-methoxy-ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Dimethylamino-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2,3-Dimethyl-3H-imidazo[4,5-b]pyridin-6-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methyl-pyridin-3-yl}-N-methyl-methanesulfonamide; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methyl-pyridin-3-yl}-methanesulfonamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[4-(1H-imidazol-2-yl)-phenyl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(2-methyl-imidazol-1-yl)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-pyrazol-1-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(2-methylamino-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-(2-methylamino-pyrimidin-5-yl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Amino-pyrimidin-5-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Amino-pyrimidin-5-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(3-isopropoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-fluoro-3-isopropoxy-phenyl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethoxy-6-methyl-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(5-Ethoxy-6-methyl-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3,5-dimethyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-[5-(2-methoxy-ethoxy)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-methoxy-ethoxy)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-methyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-methyl-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{4-[8-(5-Ethylamino-6-methyl-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3,5-dimethyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 8-(5-Amino-6-methyl-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-methyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-methoxy-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-methoxy-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-ethoxy-pyridin-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-isopropoxy-pyridin-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Diethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-pyrrolidin-1-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(ethyl-methyl-amino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[6-(Ethyl-methyl-amino)-pyridin-3-yl]-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[6-(Ethyl-methyl-amino)-pyridin-3-yl]-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid methyl ester; {4-[8-(6-Methoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-acetic acid; 2-{4-[8-(6-Methoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N,N-dimethyl-acetamide; 1-[1-(2-Hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(2-hydroxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-(3-hydroxy-propoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethoxy-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 5-[1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carboxylic acid amide; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-2-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-2-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyrazin-2-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-{3-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-phenyl}-N-methyl-methanesulfonamide; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N,N-Dimethyl-2-{3-methyl-4-[3-methyl-8-(6-methylamino-pyridin-3-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methyl-6-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-methanesulfonamide; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-N-methyl-methanesulfonamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(2H-tetrazol-5-yl)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridine-2-carbonitrile; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinic acid; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-N-methyl-nicotinamide; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-piperazin-1-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-methoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-pyridin-3-yl-1,3-dihydro-imidazo[4,5-c]quinoline-2-thione; 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinoline-2-thione; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethoxy-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-2-methoxy-nicotinonitrile; 8-(6-Ethoxy-pyridin-3-yl)-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-8-phenyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-Ethyl-N-methyl-2-[3-methyl-4-(3-methyl-2-oxo-8-phenyl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-pyrazol-1-yl]-acetamide; 2-{4-[8-(6-Ethoxy-pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-3-methyl-pyrazol-1-yl}-N-ethyl-N-methyl-acetamide; N-(2-Methoxy-ethyl)-N-methyl-2-[3-methyl-4-(3-methyl-2-oxo-8-phenyl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-pyrazol-1-yl]-acetamide; 1-[1-(2-Azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(6-ethoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N,N-Diethyl-2-{3-methyl-4-[3-methyl-8-(6-methyl-pyridin-3-yl)-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide; N-Ethyl-N-methyl-2-{3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Fluoro-6-methylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-fluoro-6-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Fluoro-6-methylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-fluoro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-fluoro-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-fluoro-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-(6-trideuteromethylamino-5-trifluoromethyl-pyridin-3-yl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-8-(6-methylamino-5-trifluoromethyl-pyridin-3-yl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-5-trifluoromethyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methylamino-5-trifluoromethyl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethylamino-5-trifluoromethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethylamino-5-trifluoromethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-methylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-methylamino-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-methylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-methylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-methylamino-pyridin-3-yl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-methylamino-pyridin-3-yl)-1-(3,5-dimethyl-isoxazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-ethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-chloro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-chloro-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-chloro-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-chloro-pyridin-3-yl)-1-(3,5-dimethyl-isoxazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-fluoro-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-fluoro-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-fluoro-pyridin-3-yl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-fluoro-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-fluoro-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Dimethylamino-6-fluoro-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-chloro-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-chloro-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-chloro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Chloro-5-ethylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Chloro-5-ethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Chloro-5-ethylamino-pyridin-3-yl)-1-(3,5-dimethyl-isoxazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-fluoro-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3,5-Dimethyl-isoxazol-4-yl)-8-(5-ethylamino-6-fluoro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-hydroxymethyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-hydroxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-methoxymethyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Hydroxymethyl-5-methylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-5-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-isopropylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(6-methyl-5-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Dimethylamino-6-methyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(ethyl-methyl-amino)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-ethoxymethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-ethoxymethyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-ethoxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-ethoxymethyl-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-ethoxymethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxymethyl-6-ethylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-methoxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-methoxymethyl-pyridin-3-yl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-methoxymethyl-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-hydroxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-hydroxymethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Amino-5-hydroxymethyl-pyridin-3-yl)-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-6-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Hydroxymethyl-6-methylamino-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Cyclobutylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(isopropyl-methyl-amino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[5-(Cyclobutyl-methyl-amino)-pyridin-3-yl]-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(5-morpholin-4-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-methyl-8-(5-morpholin-4-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-[1-(2-Hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-8-(5-morpholin-4-yl-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(ethyl-methyl-amino)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Isopropylamino-pyridin-3-yl)-1-[1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Dimethylamino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Azetidin-1-yl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(5-methylamino-pyridin-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-1-fluoromethyl-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Difluoromethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-hydroxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(2,5-Dimethyl-2H-pyrazol-3-yl)-8-(5-hydroxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-ethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-hydroxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-1-fluoromethyl-ethoxy)-6-methyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(5-isopropoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-fluoro-1-fluoromethyl-ethoxy)-6-hydroxymethyl-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Hydroxymethyl-5-methoxy-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-hydroxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-ethoxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethoxymethyl-5-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethoxy-6-methoxymethyl-pyridin-3-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-trideuteromethoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-methoxy-6-trideuteromethoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-hydroxymethyl-6-methoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(6-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5,6-Dimethoxy-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-[1-(2-Azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(5-isopropoxy-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethylamino-5-methoxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(6-Ethylamino-5-methoxymethyl-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2-Dimethylamino-pyrimidin-5-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-6-ethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(6-ethyl-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethylamino-6-methyl-pyridin-3-yl)-1-[1-(2-hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-[1-(2-Hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-8-(5-methoxy-6-methyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Ethoxy-6-methyl-pyridin-3-yl)-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((R)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((R)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[5-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-ethyl-1-hydroxy-propyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; (rac)-1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-hydroxy-cyclopentyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-[5-(2-Fluoro-1-fluoromethyl-1-hydroxy-ethyl)-pyridin-3-yl]-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionitrile; 2-{5-[1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionitrile; 2-{5-[1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionitrile; 1-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-cyclobutanecarbonitrile; 1-{5-[1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-cyclobutanecarbonitrile; N-{2-Chloro-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-acetamide; N-{2-Chloro-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-methanesulfonamide; 2-Amino-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-nicotinamide; 2-Amino-5-[1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-methyl-nicotinamide; 2-Amino-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-isopropyl-nicotinamide; 2-Amino-5-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-(2-methoxy-ethyl)-nicotinamide; 2-Amino-N-ethyl-5-[1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-nicotinamide; 2-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-N-methyl-acetamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(2-hydroxy-1,1-dimethyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 2-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-yl}-2-methyl-propionic acid methyl ester; 8-(5-Aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N-{5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-pyridin-3-ylmethyl}-acetamide; 8-(5-Aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-8-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(2-ethylamino-4-methoxy-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(4-methoxy-2-methylamino-pyrimidin-5-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(1-ethyl-2-oxo-1,4-dihydro-2H-pyrido[3,2-d][1,3]oxazin-7-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Chloro-6-hydroxymethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-methoxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[5-(1-ethoxy-1-methyl-ethyl)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(6-(methylamino)pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-2(3H)-thione; 5-[1-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-N-ethyl-2-methylamino-nicotinamide; N-Ethyl-2-methylamino-5-[3-methyl-2-oxo-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl]-nicotinamide; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-ethoxy-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-[6-hydroxymethyl-5-(2-methoxy-ethoxy)-pyridin-3-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Allyl-8-(5-amino-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; N,N-Diethyl-2-{3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetamide; {3-Methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetic acid; 1-[1-(2-Azetidin-1-yl-2-oxo-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-[3-methyl-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrazol-4-yl]-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-[3-methyl-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 3-Methyl-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Isopropyl-3-methyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-6-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1-Ethyl-3-methyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-6-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-6-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 1-(3-Chloro-1-methyl-1H-pyrazol-4-yl)-8-(5-methoxymethyl-6-methylamino-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(5-Methoxymethyl-6-methylamino-pyridin-3-yl)-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one; 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-ethyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(2,5-dimethyl-2H-pyrazol-3-yl)-3-methyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one; 8-(3,4-Dimethoxy-phenyl)-1-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one; or a pharmaceutically acceptable salt thereof.
 5. A compound, or a pharmaceutically acceptable salt thereof, selected from:


6. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a further therapeutic agent, together with a pharmaceutically acceptable carrier.
 7. A method of treatment of a disease comprising administration of a prophylactically or therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a warm-blooded animal in need of such treatment, wherein the disease is selected from a proliferative disease, a benign or malignant tumor, a carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, colon carcinoma or colorectal adenoma or a tumor of the neck or head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, lymphomas, a mammary carcinoma or a leukemia, Cowden syndrome, Lhermitte-Dudos disease or Bannayan-Zonana syndrome, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, psoriasis, skin fibrosis, scleroderma and keloids.
 8. The method of claim 7 wherein the administration is by topical application. 